Macrocyclic compounds for the treatment of autoimmune diseases

Abstract

The present invention relates to a compound of formula (I-2), TIFF2026522985000201.tif75161 (wherein R 1 ~R 3 , Q 1 , Q 2 , A 1 ~A 7 , and M 1 are as described herein) and pharmaceutically acceptable salts thereof, and to compositions containing the above compounds and methods of using the above compounds.

Description

[Technical Field]

[0001] This invention relates to organic compounds useful for the treatment and / or prevention in mammals, particularly to STING antagonists useful for the treatment of autoimmune diseases. [Background technology]

[0002] Field of Invention Autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and inflammatory bowel disease (IBD) refer to a spectrum of conditions in which the immune system mistakenly attacks the body's own tissues, resulting in improperly activated, pathogenic inflammation that does not subside. Many autoimmune diseases cannot be adequately controlled by existing treatments that only provide symptom relief. Steroids and broad immunosuppressants (e.g., mycophenolate and cyclophosphamide) constitute standard treatment but come with significant treatment-related toxicity. Pathway selectors such as adalizumab (anti-TNF antibody, for RA and IBD) occasionally lead to infection or inadequate tumor surveillance. Belimumab (anti-BAFF antibody, the only FDA-approved novel drug for SLE) also has a slow remission induction and limited clinical efficacy. Furthermore, the diversity of many autoimmune diseases for which there are no existing treatments highlights the difficulty of finding efficacy by blocking a single immune pathway. Therefore, currently available treatments fail to meet the greater unmet needs of autoimmune inflammatory diseases, resulting in limited remission, serious side effects, opportunistic infections, and a reduced quality of life accompanied by chronic inflammation.

[0003] Interferon gene stimulators (STINGs) are transmembrane proteins located in the endoplasmic reticulum (ER) that play a crucial role in mediating the host's innate sensing of pathogen / damage-associated molecular patterns (PAMPs or DAMPs). In particular, the cyclic GMP-AMP synthase (cGAS)-STING pathway has been identified as a key mechanism for linking cytosolic DNA recognition to the induction of type I interferons (IFNs) and a broader immune defense program. Binding of cGAS to double-stranded DNA (dsDNA) allosterically activates its catalytic site, leading to the production of 2'3'-cyclic GMP-AMP (cGAMP), a secondary messenger molecule for the agonist STING. Upon activation, STING translocates from the ER to the Golgi apparatus, recruiting tank-binding kinase 1 (TBK1). TBK1 then phosphorylates interferon regulator 3 (IRF3) and nuclear factor kappa B (NF-κB), initiating the expression of type I IFN and numerous pro-inflammatory cytokines (e.g., IL-6 and TNFα), respectively. Besides 2'3'-cGAMP, STING can be activated by other types of cyclic dinucleotides (CDNs), including bacterial c-di-AMP, c-di-GMP, and 3',3'-cGAMP. Following signaling, STING is rapidly degraded, preventing constitutive signaling of the inflammatory response.

[0004] While inducing robust host defense responses, abnormal STING signaling promotes dysregulated immune responses associated with many disease states. Gain-of-function (GoF) human STING mutations are the underlying cause of infant-onset STING-associated vascular disease (SAVI), a monogenetic disorder characterized by the development of autoinflammatory conditions known as type I interferon disorders. Mechanistically, disease-causing substitutions lead to ligand-independent constitutive STING activation. Furthermore, STING is involved in DNA-driven inflammation, such as Eicardi-Goutier syndrome (AGS) and the genetic form of lupus known as familial chilblain-like lupus (FCL). Unlike SAVI, the STING-mediated, continuous innate immune activation in AGS is caused by auto-DNA clearance and metabolic deficiencies resulting from mutations in the endonuclease genes TREX1 and / or DNASE2. Consistently, genetic and pharmacological inhibition of STING improves systemic inflammation and morbidity in Trex1- / - mouse models. In addition, mutations in proteins such as COP and WAS proteins that regulate the intracellular transport and signaling of STING also indicate monogenic disorders known as COPA syndrome and Wiskott-Aldrich syndrome, respectively. Apart from the genetic disorders, robust preclinical and clinical evidence supports a general pathogenic role of STING in a range of inflammation-related disorders, including but not limited to: SLE, IBD, RA, dermatomyositis, diabetic nephropathy (DKD), age-related macular degeneration (AMD), diabetic retinopathy (DR), and antineutrophilic cytoplasmic autoantibody (ANCA)-associated vasculitis. For example, a direct link between the cGAS-STING pathway and SLE was established by observing that PBMCs derived from a subset of SLE patients had elevated cytoplasmic cGAMP compared to healthy controls. Furthermore, membrane vesicles derived from apoptotic cells in SLE serum possess high ISG-stimulating activity that is dependent on cGAS-STING. Also, disruption of STING signaling improved the development of lupus-like phenotypes in FcγrIIb- / - mice. Furthermore, several recent studies link STING to different types of neurodegeneration.Taking Parkinson's disease as an example, missense mutations in PARKIN and PINK led to the accumulation of mitochondrial DNA that caused neuron inflammation in a cGAS-STING-dependent manner. Furthermore, cGAS- and cGAMP-independent modes of STING activation also affected neuropathology and provided therapeutic targets for the treatment of Niemann-Pick disease type C (NPC). The absence of STING restored motor deficits and neuronal loss in mouse disease models. Finally, STING also mediated the tumorigenic DNA response caused by chromosomal instability during cancer metastasis, and its STING deficiency prevented colorectal and skin cancers in mice.

Summary of the Invention

[0005] Summary of the Invention The present invention relates to novel compounds of formula (I-2),

Chemical Formula

Chemical Formula

Chemical Formula

Chemical Formula

[0006] Another object of the present invention relates to novel compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2). Their preparation, pharmaceuticals based on the compounds according to the invention and their preparation, and the use of the compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) as STING antagonists, and for the treatment or prevention of autoimmune diseases, inflammatory diseases, neuropathic diseases, metabolic diseases, cardiovascular diseases, or certain types of cancer in which overexpression or activation of STING is involved. The compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) exhibit excellent STING antagonistic activity. Furthermore, the compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) also exhibit good cytotoxicity, phototoxicity, solubility, hPBMC, metabolic stability, hERG and SDPK profiles, and low CYP inhibition. BRIEF DESCRIPTION OF THE DRAWINGS

[0007] [Figure 1] X-ray crystallographic analysis of compound 46a-1. [Figure 2] X-ray crystallographic analysis of compound 67b. DETAILED DESCRIPTION OF THE INVENTION

[0008] DETAILED DESCRIPTION OF THE INVENTION DEFINITIONS The term "dueterio" or "deuterium" means an isotope of hydrogen having a single neutron as well as a proton in the nucleus.

[0009] "C 1-6 alkyl" means a saturated straight-chain or branched-chain alkyl group containing 1 to 6, especially 1 to 4 carbon atoms, for example, methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, tert-butyl and the like. Certain "C 1-6 alkyl" groups are methyl, ethyl, and n-propyl.

[0010] "C 1-6 alkylene" means a divalent C1-6 It means alkyl. 1-6 Examples of alkylene groups include methylene, ethylene, propylene, 2-methylpropylene, butylene, 2-ethylbutylene, pentylene, and hexylene.

[0011] "C 1-6 The term "alkoxy" is C 1-6 It means alkyl-O-.

[0012] The terms "halogen" and "halo" are used interchangeably herein and mean fluoro, chloro, bromo, or iodine.

[0013] "Hello C 1-6 The term "alkyl" is C 1-6 C in which at least one hydrogen atom of the alkyl group is replaced by the same or a different halogen atom, in particular a fluoro atom. 1-6 This refers to an alkyl group. Examples of haloalkyl groups include monofluoro-, difluoro-, or trifluoro-methyl, -ethyl, or -propyl, such as 3,3,3-trifluoropropyl, 2-fluoroethyl, 2,2,2-trifluoroethyl, fluoromethyl, or trifluoromethyl.

[0014] "Hello C 1-6 The term "alkoxy" is a halo C 1-6 It means alkyl-O-.

[0015] "C 3-7 The term "cycloalkyl" refers to a monovalent saturated monocyclic or bicyclic hydrocarbon group containing 3 to 7 ring carbon atoms. Bicyclic means consisting of two saturated carbon rings, each having one or more carbon atoms in common. Examples of monocyclic cycloalkyls are cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, or cycloheptyl. Examples of bicyclic cycloalkyls are bicyclo[1.1.0]butyl, bicyclo[2.2.1]heptanyl, bicyclo[1.1.1]pentanyl, or bicyclo[2.2.2]octanyl.

[0016] "C 3-7 The term "cycloalkylene" refers to a divalent C 3-7 It means cycloalkyl.

[0017] The term "oxetanilen" refers to the divalent oxetanyl.

[0018] The terms “heterocyclic group,” “heterocyclic formula,” “heterocyclic,” “heterocyclic,” or “heterocyclo” are used interchangeably and refer to any monocyclic, dicyclic, tricyclic, spiro, or bridging saturated, partially saturated, or unsaturated non-aromatic cyclic system having 3 to 20 ring atoms, where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, oxygen, or silicon. If any of the ring atoms in the cyclic system is a heteroatom, the system is a heterocycle regardless of the bond points of the cyclic system to the rest of the molecule. For example, a heterocyclil includes monocyclic, dicyclic, tricyclic, spiro, and bridging cyclic systems containing 3 to 11 ring atoms ("members"), where the ring atoms are carbon and at least one atom in the ring or cyclic system is a heteroatom selected from nitrogen, sulfur, oxygen, or silicon. In other examples, a heterocyclil contains 4 to 10 or 5 to 10 ring atoms. For example, a heterocyclil contains 1 to 4 heteroatoms. In one example, the heterocyclyl contains 1 to 3 heteroatoms. In another example, the heterocyclyl contains a 3- to 7-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen, or silicon. In yet another example, the heterocyclyl contains a 4- to 6-membered monoring having 1 to 2, 1 to 3, or 1 to 4 heteroatoms selected from nitrogen, sulfur, oxygen, or silicon. In yet another example, the heterocyclyl contains a 3-membered monoring. In yet another example, the heterocyclyl contains a 4-membered monoring. In yet another example, the heterocyclyl contains a 5- to 6-membered monoring. In some embodiments, the heterocycloalkyl contains at least one nitrogen. In one example, the heterocyclyl group contains 0 to 3 double bonds. Any nitrogen or sulfur heteroatoms may be oxidized (e.g., NO, SO, SO2), and any nitrogen heteroatoms may be quaternized (e.g., [NR4]). +Cl - 、[NR4] + OH -Examples of heterocycles include oxyranyl, azilidinyl, thiranyl, azetidinyl, oxetanyl, thietanyl, 1,2-dithietanyl, 1,3-dithietanyl, pyrrolidinyl, dihydro-1H-pyrrolyl, dihydrofuranyl, tetrahydrofuranyl, dihydrothienyl, tetrahydrothienyl, imidazolidinyl, piperidinyl, piperazinyl, isoquinolinyl, tetrahydroisoquinolinyl, morpholinyl, thiomorpholinyl, 1,1-dioxo-thiomorpholinyl, dihydropyranyl, tetrahydropyranyl, hexahydrothiopyranyl, hexahydro Dropyrimidinil, oxazinanil, thiadinil, thioxanil, homopiperazinil, homopiperidinil, azepanil, oxepanil, thiepanil, oxazepinil, oxazepanil, diazepanil, 1,4-diazepanil, diazepinil, thiazepinil, thiazepanil, tetrahydrothiopyranil, oxazolidinil, thiazolidinil, isothiazolidinil, 1,1-dioxoiisothiazolidinonil, 1,1-dioxoiisothiazolyl, oxazolidinonil, imidazolidinonil, 4,5,6,7-tetrahydro[2H]indazolyl, tetrahydro Benzimidazolyl, 4,5,6,7-tetrahydrobenzo[d]imidazolyl, thiadinyl, oxazinyl, thiadiadinyl, oxadiadinyl, dithiadinyl, dioxazinyl, oxathiadinyl, thiatriazinyl, oxatriazinyl, dithiadiadinyl, imidazolinyl, dihydropyrimidyl, tetrahydropyrimidyl, 1-pyrrolinyl, 2-pyrrolinyl, 3-pyrrolinyl, indolinyl, thiapyranil, 2H-pyranil, 4H-pyranil, dioxanil, 1,3-dioxolanil, pyrazolinyl, pyrazolidinyl, dithianil, dithiolanil , pyrimidinonyl, pyrimidinedionyl, pyrimidine-2,4-dionyl, piperadinonyl, piperazinedionyl, pyrazolidinylimidazolinyl, 3-azabicyclo[3.1.0]hexanyl, 3,6-diazabicyclo[3.1.1]heptanyl, 6-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[3.1.1]heptanyl, 3-azabicyclo[4.1.0]heptanyl, azabicyclo[2.2.2]hexanyl, 2-azabicyclo[3.2.1]octanyl, 8-azabicyclo[3.2.1]octanyl, 2-azabicyclo[2.2.Examples include 2]octanyl, 8-azabicyclo[2.2.2]octanyl, 7-oxabicyclo[2.2.1]heptane, azaspiro[3.5]nonanyl, azaspiro[2.5]octanyl, azaspiro[4.5]decanyl, 1-azapiro[4.5]decane-2-onyl, azaspiro[5.5]undecanyl, tetrahydroindolyl, octahydroindolyl, tetrahydroisoindolyl, tetrahydroindazolyl, 1,1-dioxohexahydrothiopyranyl, 2,3,4a,5,7,7a-hexahydro-[1,4]dioxo[2,3-c]pyrrolyl, and oxopiperazinyl.

[0019] The term "heterocyclylene" refers to a divalent heterocyclyl group.

[0020] In certain embodiments, the heterocyclyl or heteroaryl group is bonded to a carbon atom of the heterocyclyl or heteroaryl group. Examples of carbon-bonded heterocyclyl groups include bond configurations at positions 2, 3, 4, 5, or 6 of a pyridine ring, positions 3, 4, 5, or 6 of a pyridazine ring, positions 2, 4, 5, or 6 of a pyrimidine ring, positions 2, 3, 5, or 6 of a pyrazine ring, positions 2, 3, 5, or 5 of a furan, tetrahydrofuran, thiofuran, thiophene, pyrrole, or tetrahydropyrrole ring, positions 2, 3, 4, or 5 of an oxazole, imidazole, or thiazole ring, positions 3, 4, or 5 of an isoxazole, pyrazole, or isothiazole ring, position 2 or 3 of an aziridine ring, position 2, 3, or 4 of an azetidine ring, positions 2, 3, 4, 5, 6, 7, or 8 of a quinoline ring, or positions 1, 3, 4, 5, 6, 7, or 8 of an isoquinoline ring.

[0021] In certain embodiments, the heterocyclyl or heteroaryl group is nitrogen-bonded. Examples of nitrogen-bonded heterocyclyl or heteroaryl groups include those at position 1 of aziridine, azetidine, pyrrole, pyrrolidine, 2-pyrroline, 3-pyrroline, imidazole, imidazolidine, 2-imidazoline, 3-imidazoline, pyrazole, pyrazoline, 2-pyrazoline, 3-pyrazoline, piperidine, piperazine, indole, indoline, at position 1 of 1H-indazole, at position 2 of isoindole or isoindoline, at position 4 of morpholine, and at position 9 of carbazole or β-carbolin.

[0022] Unless otherwise specified, the term “may be substituted” means that a group may be unsubstituted or may be substituted with one or more substituents listed for that group (e.g., 0, 1, 2, 3, 4, or 5 or more, or any range that can be derived from there) (the substituents may be the same or different). In one embodiment, the may be substituted group has one substituent. In another embodiment, the may be substituted group has two substituents. In another embodiment, the may be substituted group has three substituents. In another embodiment, the may be substituted group has four substituents. In another embodiment, the may be substituted group has five substituents.

[0023] Suitable substituents for the "may be substituted" group include deuterio, halogen, cyano, carboxy, R, RO, RS, RNH, (R)2N, RCO, RSO2, RNHSO2, R2NSO2, RSO(NR), R3Si, and ROC. 1-6 Alkyl, RSC 1-6 Alkyl, RNHC 1-6 Alkyl, (R)2NC 1-6 Alkyl, RSO2C 1-6 Alkyl, RNHSO2C 1-6 Alkyl, R2NSO2C 1-6 Alkyl, RSO(NR)C 1-6 Alkyl and R3SiC 1-6 It is an alkyl group, where R is H, Ra , R b or R c And R a R b or R c Even if replaced by C 1-6 It is alkyl, R b C 3-7 The C 3-7 Cycloalkyls, heterocyclyls, heteroaryls, and aryls are either unsubstituted or deuterios, halogens, or R c It may also be replaced with R c Deuterio, C 1-6 Alkyl, (C 1-6 Alkyl)3Si, Halo C 1-6 Alkyl, deuterio C 1-6 Alkyl, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, Deuterio C 1-6 Alkoxy, C 2-6 Alkenil, Halo C 2-6 Alkenil, Deuterio C 2-6 Alkenil, C 2-6 Alkinil, Halo C 2-6 Alkinil, Deuterio C 2-6 Alkinyl, C 3-7 Cycloalkyl, Halo C 3-7 Cycloalkyl, deuterio C 3-7 Cycloalkyl, amino, C 1-6 Alkylamino, (C 1-6 Alkyl)2-amino, C 1-6 Alkylcarbonylamino, Halo C 1-6 Alkylamino, Halo C 1-6 Alkylcarbonylamino, (Halo C 1-6 Alkyl)2-amino, C 3-7 Cycloalkylamino, C 3-7 Cycloalkylcarbonylamino, (C 3-7 Cycloalkyl)2-amino, Halo C 3-7 Cycloalkylamino, (Halo C 3-7 Cycloalkyl)2-amino, C 3-7Cycloalkyl (C 1-6 Alkyl)amino, Halo C 3-7 Cycloalkyl (C 1-6 Alkyl)amino, C 1-6 Alkyl sulfonyl amino acids, Halo C 1-6 Alkylsulfonylamino, C 1-6 Alkoxy C 1-6 Alkyl, (halo C 1-6 Alkoxy)C 1-6 Alkyl, C 1-6 Alkoxy(halo)C 1-6 Alkyl, C 3-7 Cycloalkyl C 1-6 Alkyl, C 3-7 Cycloalkylhalo C 1-6 Alkyl, C 1-6 Alkylcarbonyl, Halo C 1-6 Alkylcarbonyl, C 3-7 Cycloalkylcarbonyl, Halo C 3-7 Cycloalkylcarbonyl, C 1-6 Alkoxycarbonyl, Halo C 1-6 Alkoxycarbonyl, C 3-7 Cycloalkoxycarbonyl, Halo C 3-7 Cycloalkoxycarbonyl, C 1-6 Alkylaminocarbonyl, (C 1-6 Alkyl)2-aminocarbonyl, C 3-7 Cycloalkylaminocarbonyl, (C 3-7 Cycloalkyl)2-aminocarbonyl, C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, Halo C 1-6 Alkylaminocarbonyl, Halo(C) 1-6 Alkyl)2-aminocarbonyl, Halo C 3-7 Cycloalkylaminocarbonyl, Halo(C 3-7 Cycloalkyl)2-aminocarbonyl, Halo C 1-6 Alkyl C 3-7 Cycloalkylaminocarbonyl, C 1-6 Alkylhalo C 3-7 Cycloalkylaminocarbonyl, (C 1-6 Alkyl)3-Ammonia, C 1-6Alkyl sulfanyl, C 1-6 Alkyl sulfinyl, C 1-6 Alkyl sulfonyl, C 3-7 Cycloalkylsulfanyl, C 3-7 Cycloalkylsulfinyl, C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkyl sulfanyl, Halo C 1-6 Alkyl sulfinyl, Halo C 1-6 Alkyl sulfonyl, Halo C 3-7 Cycloalkylsulfanyl, Halo C 3-7 Cycloalkylsulfinyl, Halo C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkoxysulfonyl, C 1-6 Alkylaminosulfonyl, (Halo C 1-6 Alkylamino)sulfonyl, (C 1-6 Alkyl)2-aminosulfonyl, (halo C 1-6 Alkyl)2-aminosulfonyl, (C 1-6 (Alkyl)2 phosphoryl, (C 1-6 Alkoxy)2 phosphoryl, hydroxy(C 1-6 Alkoxy) phosphoryl, C 1-6 Alkoxyphosphoryl, hydroxy, hydroxyC 1-6 Alkyl, hydroxyhalo C 1-6 Alkyl, hydroxy C 1-6 Alkoxy, hydroxyhalo C 1-6 Alkoxy, Hydroxy C 3-7 Cycloalkyl, hydroxyhalo C 3-7 Selected from cycloalkyl and sulfonimidoyl, with H, halogen, and C respectively. 1-6 Alkyl, C 1-6 Substituted with alkoxy, aryl, heteroaryl, or heterocyclyl compounds.

[0024] The term "PG" stands for protecting group.

[0025] The terms "cis" and "trans" refer to the relative stereochemistry of a molecule or part. For example, the trans-cyclopentane-1,3-diamine used in the synthesis of Example 4 has a trans isomer: [ka] and [ka] This refers to a mixture of these. Methods for demonstrating relative stereochemistry are also applied to the final compound.

[0026] The term "pharmaceutically acceptable salt" refers to a salt that is not biologically or otherwise undesirable. pharmaceutically acceptable salts include both acid addition salts and base addition salts.

[0027] The term "pharmaceutically acceptable acid addition salt" refers to a pharmaceutically acceptable salt formed by an organic acid selected from aliphatic, alicyclic, aromatic, araliphatic, heterocyclic, carboxylic acid, and sulfonic acid derivatives, such as an inorganic acid like hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, carbonic acid, or phosphoric acid, and an organic acid like formic acid, acetic acid, propionic acid, glycolic acid, gluconic acid, lactic acid, pyruvic acid, oxalic acid, malic acid, maleic acid, maloneic acid, succinic acid, fumaric acid, tartaric acid, citric acid, aspartic acid, ascorbic acid, glutamic acid, anthranilic acid, benzoic acid, cinnamic acid, mandelic acid, embonic acid, phenylacetic acid, methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid, and salicylic acid.

[0028] The term "pharmaceutically acceptable base addition salt" refers to a pharmaceutically acceptable salt formed with an organic or inorganic base. Examples of acceptable inorganic bases include sodium salts, potassium salts, ammonium salts, calcium salts, magnesium salts, iron salts, zinc salts, copper salts, manganese salts, and aluminum salts. Salts obtained from pharmaceutically acceptable organic non-toxic bases include salts of primary, secondary, and tertiary amines, substituted amines including naturally substituted amines, cyclic amines, and basic ion exchange resins, such as isopropylamine, trimethylamine, diethylamine, triethylamine, tripropylamine, ethanolamine, 2-diethylaminoethanol, trimamine, dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine, hydravamine, choline, betaine, ethylenediamine, glucosamine, methylglucamine, theobromine, purine, piperazine, piperidine N-ethylpiperidine, and polyamine resins.

[0029] The term "pharmaceutically active metabolite" refers to pharmacologically active products produced through the metabolism of a particular compound or a salt thereof in the body. After entering the body, most drugs become substrates for chemical reactions, which can alter their physical properties and biological effects. These metabolic transformations typically affect the polarity of the compounds in this invention and alter how the drug is distributed within and excreted from the body. However, in some cases, the metabolism of a drug is necessary for its therapeutic effect.

[0030] The term "therapeutic dose" means the amount of the compound or molecule of the present invention, when administered to a subject, that (i) treat or prevent a particular disease, condition, or disorder; (ii) reduce, improve, or eliminate one or more symptoms of a particular disease, condition, or disorder; or (iii) prevent or delay the onset of one or more symptoms of a particular disease, condition, or disorder as described herein. The therapeutic dose varies depending on the compound, the condition being treated, the severity of the disease being treated, the age and relative health status of the subject, the route and form of administration, the judgment of the attending physician or veterinarian, and other factors.

[0031] The term "pharmaceutical composition" means a mixture or solution containing a therapeutically effective amount of an active pharmaceutical ingredient together with pharmaceutically acceptable additives, which is administered to a mammal, for example, a human being in need.

[0032] The terms “pharmaceutically acceptable additive,” “pharmaceutically acceptable carrier,” and “therapeutically inactive additive” are interchangeable and refer to any pharmaceutically acceptable component in a pharmaceutical composition that is non-therapeutic and non-toxic to the target of administration, used in the formulation of pharmaceutical products, such as disintegrants, binders, fillers, solvents, buffers, isotonic agents, stabilizers, antioxidants, surfactants, carriers, diluents, or lubricants.

[0033] STING's Antagonist The present invention relates to (i) a compound of formula (I-2), [ka] (In the formula, R 1 H, C 1-6 Alkyl or R 9 Together with it, it forms a heterogeneous ring which may be substituted, R 2 C 1-6 Alkyl or R 9 Together with, it forms a complex ring which may be substituted, M 1 is a heterocyclylene that may be substituted, and further R 3 Replaced by, R 3 teeth, [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] , [ka] [ka] [ka] [ka] [ka] [ka] [ka] or [ka] And in the formula, R 4H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, C 1-6 Alkyl, Halo C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkylcarbonyl, C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkyl, Halo C 1-6 Alkylcarbonyl, HydroxyC 3-7 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl, R 5 is halogen, C 1-6 Alkoxy, C 1-6 Alkyl NH, Halo C 1-6 Alkoxy, C 3-7 Cycloalkoxy and Triduterio C 1-6 A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R 6 is H or C 1-6 It is alkyl, A 1 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 2 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 3 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 4 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 5 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 6 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 7 is N or CR 7 And in the formula, R 7 H, C 1-6 Alkyl, C 1-6 It is an alkoxy or halogen, A 8 is N and A 9 Is it C, or A? 8 C is A 9 Is it N, or A? 8 C is A 9 C is, Q 1 CR 8 R 9 , a heterogeneous ring that may be substituted, C 3-7 It is a cycloalkylene or oxetarnylene, in which, R 8H, OH, C 1-6 Alkoxy, halogen, CN, C 1-6 Alkyl, Halo C 1-6 It is alkyl, or R 9 Together with this, a substituted heteroalgebra or a substituted C 3-7 Forming a cycloalkyl ring, R 9 H, OH, C 1-6 Alkoxy, halogen, CN, C 1-6 Alkyl, Halo C 1-6 Alkyl or R 1 Or R 2 It may form a heterocycle together with or substituted with R 8 A heterogeneous ring or a C that may be substituted together with it 3-7 Forming a cycloalkyl ring, Q 2 It is CH2, NH, S, or O, m is 0, 1, 2, or 3. n is 0, 1, or 2. or relating to a pharmaceutically acceptable salt thereof.

[0034] Another embodiment of the present invention is (ii) a compound of formula (I), [ka] (In the formula, R 1 H, C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 2 C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 3 teeth, [ka] And in the formula, R 4H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, C 1-6 Alkyl, Halo C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkylcarbonyl, C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkyl, Halo C 1-6 Alkylcarbonyl, HydroxyC 3-7 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl, R 5 is halogen, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-7 Cycloalkoxy and Triduterio C 1-6 A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R 6 H is, A 1 N is, A 2 is CH or N, A 3 CH is, A 4 CH is, A 5 CH is, A 6 CR 7 And in the formula, R 7 is H or halogen, A 7 CH is, A 8 is N and A 9 Is it C, or A? 8 C is A 9 is N, Q 1 CR 8 R 9 , C 3-7 It is a cycloalkylene or oxetarnylene, in which, R 8 is either H or R 9 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, R 9 R 1 or R 2 Together with R, they form a heterocycle, or 8 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, Q 2 NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

[0035] Another embodiment of the present invention is (iii) a compound of formula (Ia), [ka] (In the formula, R 1 H, C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 2 C 1-6 Alkyl or R 9Together with it, it forms a complex ring, R 3 teeth, [ka] And in the formula, R 4 H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, C 1-6 Alkyl, Halo C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkylcarbonyl, C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkyl, Halo C 1-6 Alkylcarbonyl, HydroxyC 3-7 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl, R 5 is halogen, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-7 Cycloalkoxy and Triduterio C 1-6 A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R6 H is, A 1 N is, A 2 is CH or N, A 3 CH is, A 4 CH is, A 5 CH is, A 6 CR 7 And in the formula, R 7 is H or halogen, A 7 CH is, A 8 is N and A 9 Is it C, or A? 8 C is A 9 is N, Q 1 CR 8 R 9 , C 3-7 It is a cycloalkylene or oxetarnylene, in which, R 8 is either H or R 9 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, R 9 R 1 or R 2 Together with R, they form a heterocycle, or 8 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, Q 2 NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. a compound described in (i) or (ii), or a pharmaceutically acceptable salt thereof.

[0036] Another embodiment of the present invention is (iv) a compound of formula (I-1), [ka] (In the formula, R 1 H, C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 2 C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 3 teeth, [ka] And in the formula, R 4 H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, C 1-6 Alkyl, Halo C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkylcarbonyl, C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkyl, Halo C 1-6 Alkylcarbonyl, HydroxyC 3-7 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl, R 5 is halogen, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-7 Cycloalkoxy and Triduterio C 1-6 A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R 6 H is, A 1 N is, A 2 is CH or N, A 3 CH is, A 4 CH is, A 5 CH is, A 6 CR 7 And in the formula, R 7 is H or halogen, A 7 CH is, Q 1 CR 8 R 9 , C 3-7 It is a cycloalkylene or oxetarnylene, in which, R 8 is either H or R 9 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, R 9 R 1 or R 2 Together with R, they form a heterocycle, or 8 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, Q 2 NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. The compound is one of the compounds described in any one of (i) to (iii), or a pharmaceutically acceptable salt thereof.

[0037] Further embodiments of the present invention include (v) a compound of formula (I-1a), [ka] (In the formula, R 1 H, C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 2 C 1-6 Alkyl or R 9 Together with it, it forms a complex ring, R 3 teeth, [ka] And in the formula, R 4 H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, C 1-6 Alkyl, Halo C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkylcarbonyl, C 3-7 Cycloalkylsulfonyl, Halo C 1-6 Alkyl, Halo C 1-6 Alkylcarbonyl, HydroxyC 3-7 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl, R 5 is halogen, C 1-6 Alkoxy, Halo C 1-6 Alkoxy, C 3-7 Cycloalkoxy and Triduterio C 1-6 A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R 6 H is, A 1 N is, A 2 is CH or N, A 3 CH is, A 4 CH is, A 5 CH is, A 6 CR 7 And in the formula, R 7 is H or halogen, A 7 CH is, Q 1 CR 8 R 9 , C 3-7 It is a cycloalkylene or oxetarnylene, in which, R 8 is either H or R 9 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, R 9 R 1 or R 2 Together with R, they form a heterocycle, or 8 Together with a complex algebra or C 3-7 Forming a cycloalkyl ring, Q 2 NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

[0038] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (vi)(i) to (v), or pharmaceutically acceptable salts thereof, and R 1 C 1-6 Alkyl or R 9 Together with R, it forms a complex ring, in the formula, 1 is C 1-6 It is alkylene, R 9 is -C 1-6 It is alkylene-O-.

[0039] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (vii) to (vi), where R 1 Is it methyl, or R 9 Together with R, they form a complex ring. 1 is methylene, and R 9 It is -methylene-O-.

[0040] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (viii)(i) to (vii), or pharmaceutically acceptable salts thereof, R 2 C 1-6 Alkyl or R 9 Together with R, it forms a complex ring, in the formula, 2 is C 1-6 It is alkylene, R 9 is a bond, O or -C 1-6 It is alkylene-O-.

[0041] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (ix)(i) to (viii), or pharmaceutically acceptable salts thereof, R 2Is it methyl, or R 9 Together with R, it forms a complex ring, in the formula, 2 R is ethylene or propylene, 9 The bond is O or -methylene-O-.

[0042] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (x)(i) to (ix), or pharmaceutically acceptable salts thereof. R 4 However, H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, Hello C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, Hello C 1-6 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl.

[0043] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xi)(i) to (x), or pharmaceutically acceptable salts thereof, and R 4However, H, [1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo [3.1.1]heptan-6-yl, 3-cyanoazetidine-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl.

[0044] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xii)(i) to (xi), or pharmaceutically acceptable salts thereof, R 5 However, halogen, C 1-6 Alkoxy and triduterio C 1-6 This is a phenyl compound that is twice substituted with substituents independently selected from the alkoxy.

[0045] Further embodiments of the present invention include compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xiii)(i) to (xii), or pharmaceutically acceptable salts thereof, and R 5 However, it is a phenyl compound that is twice substituted with substituents independently selected from fluoro, methoxy, and triduteriomethoxy.

[0046] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xiv)(i) to (xiii), and R 5 These are 2,4-difluorophenyl, 4-fluoro-2-methoxyphenyl, or 4-fluoro-2-(triduteriomethoxy)phenyl.

[0047] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xv)(i) to (xiv), and R 7 However, it is either H or fluoro.

[0048] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xvi)(i) to (xv), and Q 1 However, CR 8 R 9 That is the case.

[0049] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xvii)(i) to (xvi), and R 8 H is H.

[0050] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xviii)(i) to (xvii), wherein m is 0, 1, or 2.

[0051] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in any one of (xix)(i) to (v), R 1 However, C 1-6 Alkyl or R 9 Together with R, it forms a complex ring, in the formula, 1 C 1-6 It is alkylene, R 9 is -C1-6 It is alkylene-O-, R 2 However, C 1-6 Alkyl or R 9 Together with R, it forms a complex ring, in the formula, 2 C 1-6 It is alkylene, R 9 is a bond, O or -C 1-6 It is alkylene-O-, R 3 but, [ka] And in the formula, R 4 H, ((Hello C 1-6 Alkyl)azetidinyl)C 1-6 Alkyl, Hello C 1-6 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C 1-6 Alkyl, C 3-7 Cycloalkyl, C 3-7 Cycloalkyl C 1-6 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, Hello C 1-6 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C 1-6 Alkoxy C 1-6 Alkyl, C 1-6 alkyl, or It is cyanoazetidinyl, R 5 is halogen, C 1-6 Alkoxy and triduterio C 1-6 A phenyl compound that is twice substituted with substituents independently selected from the alkoxy, R 6 H is, A 1 N is, A 2 is CH or N, A 3 CH is, A 4 CH is, A 5 CH is, A 6 CR 7 And in the formula, R 7 is H or halogen, A 7 CH is, Q 1 CR 8 R 9 And in the formula, R 8 H is R 9 R 1 or R 2 Together with it, it forms a complex ring, Q 2 NH is, m is 0, 1, or 2. n is 0, 1, or 2, but m and n are not both 0 at the same time in the compound. or a pharmaceutically acceptable salt thereof.

[0052] Further embodiments of the present invention are compounds of formula (I), (Ia), (I-1), (I-1a), or (I-2) as described in (xx)(xix), R 1 However, is it methyl, or R 9 Together with R, it forms a complex ring, in the formula, 1 It is methylene, and R 9 It is -methylene-O-, R 2 However, is it methyl, or R 9 Together with R, it forms a complex ring, in the formula, 2 is ethylene or propylene, and R 9 It is a bond, O or -methylene-O-, R 3 but, [ka] And in the formula, R 4 H, [1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo [3.1.1]heptan-6-yl, 3-cyanoazetidine-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl, R 5 These are 2,4-difluorophenyl, 4-fluoro-2-methoxyphenyl, or 4-fluoro-2-(triduteriomethoxy)phenyl, R 6 H is, A 1 N is, A 2 is CH or N, A 3 CH is, A 4 CH is, A 5 CH is, A 6 CR 7 And in the formula, R 7 is H or fluoro, A7 CH is, Q 1 CR 8 R 9 And in the formula, R 8 H is R 9 R 1 or R 2 Together with it, it forms a complex ring, Q 2 NH is, m is 0, 1, or 2. n is 0, 1, or 2, but m and n are not both 0 at the same time in the compound. or a pharmaceutically acceptable salt thereof.

[0053] Another embodiment (xxi) of the present invention is as follows: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1 2,6 .1 8,11 .1 13,17 .0 22,26]nonacosa-1(26),2,4,6(29),20,22,24-heptaene-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1 2,6 .1 8,11 .1 13,17 .0 22,26 ]nonacosa-1(26),2,4,6(29),20,22,24-heptaene-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-7,10,13,20,22,29-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .0 13,17 .0 23,27 ]nonacosa-1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-7,10,13,20,22,29-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .0 13,17 .0 23,27 ]nonacosa-1(26),2(29),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexaazahexacyclo[19.6.1.1 2,6 .1 8,11 .0 13,18 .0 24,28 ]Triaconta-1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexaazahexacyclo[19.6.1.1 2,6 .1 8,11 .0 13,18 .0 24,28 ]Triaconta-1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,18,20,28-hexazahexacyclo[16.6.1.1 2,6 .1 8,11 .1 13,16 .0 21,25 Octacosa-1(24),2(28),3,5,19,21(25),22-heptaen-12-one; (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 ]octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-on; (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 ]octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-on; (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazopentacyclo[15.6.1.12,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one; (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6.1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .023,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,17 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .023,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-on; (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-on; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene-11,17-zion; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,16,22,24,31-heptazahexacyclo[20.6.1.1 2,6 .1 8,11 .0 13,18 .0 25,29 ]Hentriakonta-1(29),2,4,6(31),23,25,27-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl]pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; 8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .023,27 Triconta-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidin-6-yl]azetidine-3-carbonitrile; (8S,11S,18S)-10-[6-[3-(Cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazabicyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-Difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazabicyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-(3-Cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazabicyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one A compound of formula (I), (Ia), (I-1), (I-1a), or (I-2) selected from the above, or a pharmaceutically acceptable salt thereof.

[0054] Another embodiment of the present invention (xxii) is a method for preparing the compound described in any one of (i) to (xxi), and the steps are as follows: a) Compound of formula (VI) in the presence of a base [ka] and R 3 The compound of formula (VI) and R via nucleophilic substitution with X, or in the presence of a coupling reagent. 3 Formation of the compound of formula (I) via a condensation reaction with OH, b)R 4 Compounds of (Ic) when containing a reactive primary or secondary amino group [ka] and R 4 The compound of formula (Ic) and the halide R via nucleophilic substitution with H, or in the presence of a catalyst. 4 X or XR c The compound of formula (IX) via photoredox coupling with BoC [ka] Formation, c) Compounds of formula (VIII) [ka] The process includes the formation of a compound of formula (IX) via a reaction between a halide, an acid anhydride, or an acid, In the formula, X is a halogen, and R e is a divalent substituent having a reactive primary or secondary amino group, The base in step a) is DIEA, The coupling reagent in step a) is PyBOP. The catalyst in step b) is Ir[dF(CF3)ppy]2(dtbbpy)PF6, R 1 ~R 5 Q 1 Q 2 , A 1 ~A 7 This is defined by any one of (i) to (xx).

[0055] Another embodiment (xxiii) of the present invention relates to any one of the compounds (i) to (xxi) or pharmaceutically acceptable salts thereof for use as a therapeutically active substance.

[0056] Another embodiment (xxiv) of the present invention relates to a pharmaceutical composition comprising a compound described in any one of (i) to (xxi) and a pharmaceutically acceptable excipient.

[0057] Another embodiment (xxv) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for the treatment or prevention of autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

[0058] Another embodiment of the present invention (xxvi) relates to any one of the compounds or pharmaceutically acceptable salts described in (i) to (xxi) for treating or preventing autoimmune diseases, inflammatory diseases, neurological diseases, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

[0059] Another embodiment of the present invention (xxvii) relates to the use of any one of the compounds described in (i) to (xxi) for the treatment of subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology.

[0060] Another embodiment (xxviii) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial chilblain-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Gutierrez syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

[0061] Another embodiment (xxix) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for the preparation of pharmaceuticals for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial chilblain-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Gutierrez syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

[0062] Another embodiment (xxx) of the present invention relates to the use of any one of the compounds described in (i) to (xxi) for inhibiting STING.

[0063] Another embodiment of the present invention (xxxi) relates to the use of any one of the compounds described in (i) to (xxi) for preparing a pharmaceutical product for inhibiting STING.

[0064] Another embodiment of the present invention (xxxii) relates to any one of the compounds (i) to (xxi) or pharmaceutically acceptable salts thereof when produced according to the process of (xxii).

[0065] Another embodiment of the present invention (xxxiii) relates to a method for treating or preventing an autoimmune disease, comprising administering a therapeutically effective dose of a compound defined in any one of (i) to (xxi).

[0066] Pharmaceutical composition and administration Another embodiment provides a pharmaceutical composition or drug containing the compound of the present invention and a therapeutically inert carrier, diluent, or additive, as well as a method of using the compound of the present invention to prepare such compositions and drugs. In one example, the compound of formula (I) may be formulated into a gallenical dosage form by mixing it with a physiologically acceptable carrier, i.e., a carrier that is nontoxic to the recipient at the dose and concentration used, at ambient temperature, at a suitable pH, and to a desired degree of purity. The pH of the formulation depends primarily on the specific application and the concentration of the compound, but is preferably in the range of about 3 to about 8. In one example, the compound of formula (I) is formulated in an acetate buffer at pH 5. In another embodiment, the compound of formula (I) is sterile. The compound may be stored, for example, as a solid or amorphous composition, as a lyophilized formulation, or as an aqueous solution.

[0067] The composition is formulated, administered, and given in a manner consistent with good medical practice. Factors to be considered in this context include the specific disorder being treated, the specific mammal being treated, the individual patient's clinical condition, the cause of the disorder, the site of drug delivery, the method of administration, the administration scheduling, and other factors known to the medical practitioner. The “effective dose” of the compound to be administered is regulated by such considerations and is the minimum amount required to inhibit STING interactions with IRF3, NF-κB, NLRP3, etc., in order to block downstream type I IFN and pro-inflammatory cytokine (e.g., IL-6, TNFα, ISG) production and cellular responses / states (e.g., autophagy, apoptosis, cellular senescence). For example, such a dose may be below the amount that is toxic to normal cells or the entire mammal.

[0068] In one example, the pharmaceutically effective dose of the compound of the present invention administered parenterally per single dose is in the range of about 0.1 to 1000 mg / kg, or in the range of about 0.1 to 1000 mg / kg per patient's body weight per day, with a typical initial range of 0.1 to 1000 mg / kg / day for the compound used. In another embodiment, an oral unit dosage form, such as a tablet or capsule, preferably contains about 0.1 to about 1000 mg of the compound of the present invention.

[0069] The compounds of the present invention may be administered by any suitable means, including oral, topical (including buccal and sublingual), rectal, vaginal, percutaneous, parenteral, subcutaneous, intraperitoneal, intrapulmonary, intradermal, intrathecal, and epidural, as well as intranasal administration, and, if desired for local treatment, intra-focal administration. Parenteral administration may include intramuscular, intravenous, intra-arterial, intraperitoneal, or subcutaneous administration.

[0070] The compounds of the present invention can be administered in any convenient dosage form, such as tablets, powders, capsules, solutions, dispersions, suspensions, syrups, sprays, suppositories, gels, emulsions, patches, etc. Such compositions may contain components that are conventional in pharmaceutical preparations, such as diluents, carriers, pH adjusters, sweeteners, fillers, and further activators.

[0071] Typical formulations are prepared by mixing the compound of the present invention with a carrier or additive. Suitable carriers and additives are well known to those skilled in the art and are described in detail, for example, Ansel, Howard C., et al., Ansel's Pharmaceutical Dosage Forms and Drug Delivery Systems. Philadelphia: Lippincott, Williams & Wilkins, 2004; Gennaro, Alfonso R., et al., Remington: The Science and Practice of Pharmacy. Philadelphia: Lippincott, Williams & Wilkins, 2000; and Rowe, Raymond C., Handbook of Pharmaceutical Excipients. Chicago, Pharmaceutical Press, 2005. The formulation may also contain one or more buffers, stabilizers, surfactants, wetting agents, lubricants, emulsifiers, suspending agents, preservatives, antioxidants, opacifiers, flow enhancers, processing aids, colorants, sweeteners, fragrances, flavorings, diluents, and other known additives for providing a drug (i.e., the compound of the present invention or its pharmaceutical composition) in an appealing manner or for assisting in the manufacture of a pharmaceutical product (i.e., a drug).

[0072] A suitable example of an oral dosage form is a tablet containing about 0.1 to 1000 mg of the compound of the present invention, formulated with about 0.1 to 1000 mg of anhydrous lactose, about 0.1 to 1000 mg of croscarmellose sodium, about 0.1 to 1000 mg of polyvinylpyrrolidone (PVP) K30, and about 0.1 to 1000 mg of magnesium stearate. The powdered components are first mixed together, and then mixed with a solution of PVP. The resulting composition can be dried, granulated, mixed with magnesium stearate, and compressed into tablet form using conventional equipment. An example of an aerosol formulation can be prepared, for example, by dissolving 0.1 to 1000 mg of the compound of the present invention in a suitable buffer solution, such as phosphate buffer, and optionally adding an isotonic agent, such as a salt of sodium chloride. The solution can be filtered to remove impurities and contaminants, for example, using a 0.2 micron filter.

[0073] Accordingly, one embodiment includes a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof. Further embodiments include a pharmaceutical composition comprising a compound of formula (I), a stereoisomer thereof, or a pharmaceutically acceptable salt thereof, together with a pharmaceutically acceptable carrier or additive.

[0074] Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of interferon disorders, autoimmune diseases, and inflammatory diseases. Another embodiment includes a pharmaceutical composition comprising a compound of formula (I) for use in the treatment of infectious diseases or selective types of cancer.

[0075] The following compositions A and B represent typical compositions of the present invention, but serve only as representative examples.

[0076] Composition A The compounds of the present invention can be used as active ingredients in a manner known to the extent of the present invention to produce tablets having the following composition. per tablet Active ingredient 200mg Microcrystalline cellulose 155mg Corn starch 25mg Talc 25mg Hydroxypropyl methylcellulose 20 mg 425mg

[0077] Composition B The compounds of the present invention can be used as active ingredients in a manner known to the extent of the present invention to produce capsules having the following compositions. per capsule Active ingredient: 100.0 mg Corn starch 20.0 mg Lactose 95.0 mg Talc 4.5mg Magnesium stearate 0.5 mg 220.0 mg

[0078] Indications and treatment methods The compounds of the present invention inhibit the binding of cGAMP to STING and its downstream signaling. Therefore, the compounds of the present invention are useful for blocking STING activation, signaling, downstream cytokine and chemokine production, and cellular processes such as apoptosis and autophagy. The compounds of the present invention are useful for inhibiting STING. Alternatively, the compounds of the present invention are useful for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), anti-neutrophil cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial chilblain-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Gutierrez syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome. More broadly, the compounds may be useful in treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer in which overexpression or activation of STING is involved.

[0079] In some embodiments, the compounds of the present invention are useful for treating or preventing autoimmune diseases.

[0080] In some embodiments, the compounds of the present invention are useful for treating or preventing inflammatory diseases.

[0081] In some embodiments, the compounds of the present invention are useful for the treatment or prevention of neurological disorders.

[0082] In some embodiments, the compounds of the present invention are useful for the treatment or prevention of cardiovascular disease.

[0083] In some embodiments, the compounds of the present invention are useful for treating or preventing eye diseases.

[0084] In some embodiments, the compounds of the present invention are useful for the treatment or prevention of selective types of cancer involving the overexpression or activation of STING.

[0085] Alternatively, the compounds of the present invention are useful in treating subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology. More broadly, these compounds can be used to treat all STING-dependent pathological cellular processes.

[0086] Another embodiment includes a method for treating or preventing cancer in a mammal in need of treatment or prevention, the method comprising administering to the mammal a therapeutically effective amount of a compound of formula (I), its stereoisomer, tautomer, prodrug or pharmaceutically acceptable salt thereof.

[0087] synthesis The compounds of the present invention can be prepared by any conventional means. Preferred processes for synthesizing these compounds and their starting materials are provided in the following scheme and examples. All substituents, in particular, R 1 ~R 7 Q 1 Q 2 , A 1 ~A 9Unless otherwise specified, the definitions above apply. Furthermore, unless otherwise specified, all reactions, reaction conditions, abbreviations, and symbols have meanings familiar to those skilled in the art of organic chemistry.

[0088] A general synthetic route for preparing the compound of the present invention is shown in the following scheme. Scheme 1 [ka] In the formula, R f X is either H or PG, where PG may be, for example, Boc or Cbz, and X is a halogen.

[0089] As shown in Scheme 1, the synthesis of the compounds of the present invention began with the boronic acid ester compound of formula (II). The compound of formula (III) was obtained by Suzuki coupling between the compound of formula (II) and the compound of formula (IIb) with a catalyst such as Pd(dppf)Cl2 and a base such as K2CO3. The compound of formula (III) was directly hydrolyzed in the presence of LiOH, followed by R f The compound of formula (IV) is obtained by appropriately deprotecting the compound (Boc deprotection: HCl in dioxane or TFA in DCM; Cbz deprotection: Pd / C or Pd(OH)2 / C under H2). The compound of formula (IV) is cyclized in the presence of a coupling reagent, e.g., HATU, and a base, e.g., DIPEA, to obtain the compound of formula (V). The compound of formula (VI) is obtained by Boc deprotection under the following acidic conditions (HCl in dioxane or TFA in DCM), or by catalytic hydrogenation (Pd / C or Pd(OH)2 / C under H2), or by Cbz deprotection under acidic conditions (TFA). The compound of formula (I) is converted to the compound of formula (VI) via nucleophilic substitution in the presence of a base such as DIEA. 3 It can be obtained by reaction with X. On the other hand, the compound of formula (I) can be obtained by reaction with the compound of formula (VI) and R in the presence of a coupling reagent such as PyBOP. 3 It can also be obtained by a condensation reaction with OH.

[0090] The following is a general synthetic route for preparing the compound of formula (IX). Scheme 2 [ka] In the formula, X is a halogen, and R e This is a divalent substituent having a reactive primary or secondary amino group.

[0091] The compound of formula (Ic) is R in the presence of a base, such as DIPEA. 4 H(R 4 If the compound contains a reactive primary or secondary amino group, it can react with the compound of formula (IX) directly to obtain the compound of formula (IX), or BOC-R e The compound of formula (VII) was obtained by reacting with H, and then deprotected under acidic conditions to obtain the compound of formula (VIII). The amino group of the compound of formula (VIII) reacts with a halide or acid anhydride via nucleophilic substitution, or with an acid via condensation, to provide the final compound of formula (IX). On the other hand, the compound of formula (Ic) and the halide R in the presence of a catalyst such as Ir[dF(CF3)ppy]2(dtbbpy)PF6 4 X or XR c Photo-redox coupling with BoC yields either the compound of formula (IX) directly or the intermediate compound of formula (VII), which is then deprotected under acidic conditions to obtain the compound of formula (VIII). The amino group of the compound of formula (VIII) reacts with a halide or acid anhydride via nucleophilic substitution or with an acid via condensation to provide the final compound of formula (IX).

[0092] The compounds of the present invention can be obtained as a mixture of diastereomers or enantiomers, which can be separated by methods well known in the art, such as (chiral) HPLC or SFC.

[0093] The present invention also relates to a method for preparing a compound of formula (I), comprising the following steps: a) Compound of formula (VI) in the presence of a base

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[0094] Compounds of formula (I), (Ia), (I-1), (I-1a) or (I-2) when produced according to the above method are also an object of the present invention. [Examples]

[0095] The present invention will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the present invention.

[0096] Abbreviation The present invention will be better understood by referring to the following embodiments. However, these embodiments should not be construed as limiting the scope of the present invention.

[0097] The abbreviations used in this specification are as follows: ACN: Acetonitrile Boc2O: Di-tert butyl dicarbonate BINAP: 2,2'-Bis(diphenylphosphino)-1,1'-Dinaphthalene DCM: Dichloromethane DCE: Dichloroethane DIPEA or DIEA: N,N-diisopropylethylamine DIBAL-H: Diisobutylaluminum hydride DIAD: Diisopropyl azodicarboxylate DMA: N,N-dimethylacetylamine DMAP: 4-dimethylaminopyridine DMF: N,N-dimethylformamide DMSO: Dimethyl sulfoxide DPPP: 1,3-bis(diphenylphosphin)propane EA or methoxy: ethyl acetate FA: Formic acid HATU:1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium 3-oxide hexafluorophosphate h(s) or hr(s): time hPBMC: Human peripheral blood mononuclear cell I C 50 : 50% inhibitory concentration Ir[dF(CF3)ppy]2(dtbpy)(PF6):[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine-N1,N1']bis[3,5-difluoro-2-[5-(trifluoromethyl)-2-pyridinyl-N]phenyl-C]iridium(III) hexafluorophosphate IPA: Isopropanol LCMS: Liquid Chromatography Mass Spectrometry mCPBA: Metachloroperoxybenzoic acid min(s): minutes MS: Mass spectrometry MsCl: Methanesulfonyl chloride Ms2O: Methanesulfonic anhydride NBS: N-bromosuccinimide NIS:N-iodosuccinimide NMP: N-methylpyrrolidone NiCl2.dtbbpy:[4,4'-bis(1,1-dimethylethyl)-2,2'-bipyridine]nickel(II) dichloride PE: Petroleum ether prep-HPLC: Preparative High-Performance Liquid Chromatography prep-TLC: Preparative Thin-Layer Chromatography PyBOP / BOP: (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinyl phosphate hexafluorophosphate PPh3: Triphenylphosphine Pd2(dba)3: Tris(dibenzylideneacetone)dipalladium(0) Pd(dppf)Cl 2: [1,1'-Bis(diphenylphosphino)ferrocene]dichloropalladium(II) (R)-binap:(R)-(+)-2,2'-bis(diphenylphosphin)-1,1'-binaphthalene Rf: retention coefficient rt, rt: room temperature RT: retention time RuPhos Pd G2: Second-generation chloro(2-dicyclohexylphosphino-2',6'-diisopropoxy-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) Selectfluor 1-Chloromethyl-4-fluoro-1,4-diazoniabicyclo[2.2.2]octanbis(tetrafluoroborate) SFC: Supercritical Fluid Chromatography S-Phos:2-Dicyclohexylphosphino-2',6'-Dimethoxybiphenyl TBSCl:tert-butyldimethylsilyl chloride t-BuXPhos:2-di-tert-butylphosphino-2',4',6'-triisopropylbiphenyl tBuXPhos Pd G3: Methanesulfonate (2-di-t-butylphosphinol-2',4',6'-tri-i-propyl-1,1'-biphenyl)(2'-amino-1,1'-biphenyl-2-yl)palladium(II) tBu3P-Pd-G2 Chloro[(tri-tert-butylphosphine)(2-aminobiphenyl-2-yl)palladium(II) T3P: Propylphosphonic anhydride TEA: Trimethylamine TFA: Trifluoroacetic acid TFAA: Trifluoroacetic anhydride THF: Tetrahydrofuran TLC: Thin-layer chromatography TTMSS: Tris(trimethylsilyl)silane XantPhos:4,5-bis(diphenylphosphin)-9,9-dimethylxanthene XPhos:2-Dicyclohexylphosphino-2',4',6'-Triisopropylbiphenyl XPhos Pd G2: Chloro(2-dicyclohexylphosphino-2',4',6'-triisopropyl-1,1'-biphenyl)[2-(2'-amino-1,1'-biphenyl)]palladium(II) v / v volume ratio

[0098] General experimental conditions Intermediate and final compounds were purified by flash column chromatography using one of the following instruments: i) Biotage SP1 system and Quad 12 / 25 cartridge module, or ii) ISCO combi-flash column apparatus. Silica gel brands and pore sizes: i) KP-SIL 60 Å, particle size: 40-60 μm; ii) CAS registry number: silica gel: 63231-67-4, particle size: 47-60 microns; iii) ZCX from Qingdao Haiyang Chemical Co., Ltd, pore size: 200-300 or 300-400.

[0099] The intermediates and final compounds were purified by preparative HPLC using XBridge® Prep-C18 (5 μm, OBD® 30 × 100 mm) column, SunFire® Prep-C18 (5 μm, OBD® 30 × 100 mm) column, or reverse-phase columns using Phenomenex Synergi-C18 (10 μm, 25 × 150 mm) or Phenomenex Gemini-C18 (10 μm, 25 × 150 mm). Waters AutoP purification system (Sample Manager 2767, Pump 2525, Detectors: Micromass ZQ and UV2487, Solvent system: Acetonitrile and 0.1% ammonium hydroxide aqueous solution; Acetonitrile and 0.1% FA aqueous solution or Acetonitrile and 0.1% TFA aqueous solution) or Gilson-281 purification system (Pump 322, Detector: UV156, Solvent system: Acetonitrile and 0.05% ammonium hydroxide aqueous solution; Acetonitrile and 0.225% FA aqueous solution; Acetonitrile and 0.05% HCl aqueous solution; Acetonitrile and 0.075% TFA aqueous solution; or Acetonitrile and water).

[0100] For SFC chiral separation, intermediates were separated using chiral columns (Daicel chiralpak IC, 5 μm, 30 × 250 mm), AS (10 μm, 30 × 250 mm), or AD (10 μm, 30 × 250 mm) with a Mettler Toledo Multigram III system SFC, Waters 80Q preparative SFC, or Thar 80 preparative SFC, solvent system: CO2 and IPA (0.5% TEA in IPA) or CO2 and MeOH (0.1% NH3·H2O in MeOH), back pressure of 100 bar, and detection UV at 254 or 220 nm.

[0101] The LC / MS spectra of the compounds were obtained using LC / MS (Waters® Alliance 2795-Micromass ZQ, Shimadzu Alliance 2020-Micromass ZQ, or Agilent Alliance 6110-Micromass ZQ), with the following LC / MS conditions (trial time 3 minutes or 1.5 minutes). Acidic conditions I: A: 0.1% TFA in H2O; B: 0.1% TFA in acetonitrile; Acidic conditions II: A: 0.0375% TFA in H2O; B: 0.01875% TFA in acetonitrile; Basic conditions I: A: 0.1% NH3·H2O in H2O; B: Acetonitrile; Basic conditions II: A: 0.025% NH3·H2O in H2O; B: Acetonitrile; Neutral conditions: A: H2O; B: Acetonitrile. Mass spectra (MS): Generally, only ions showing the primary mass are reported, and unless otherwise stated, the cited mass ions are positive mass ions (MH). + That is the case.

[0102] NMR spectra were acquired using Bruker Avance 400MHz and 500MHz.

[0103] Microwave-assisted reactions were carried out using a Biotage Initiator Sixty microwave synthesizer. All reactions involving air-sensitive reagents were performed under an argon or nitrogen atmosphere. Unless otherwise specified, commercially available reagents were used without further purification.

[0104] Preparation Examples The following examples are intended to illustrate the meaning of the present invention, but are not intended to limit it within the scope of the present invention.

[0105] Intermediate A1 tert--butyl6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]methyl]-1,4-oxazepan-4-carboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0106] Step 1: Preparation of tert-butyl 6-[(2-bromo-6-nitroanilino)methyl]-1,4-oxazepane-4-carboxylate (intermediate A1-a) A mixture in acetonitrile (20 mL) containing 1-bromo-2-fluoro-3-nitrobenzene (1.38 g, 6.25 mmol, as "aryl fluoride" in Table 1), tert-butyl 6-(aminomethyl)-1,4-oxazepane-4-carboxylate (1.2 g, 5.21 mmol, as "amine" in Table 1), and K2CO3 (1.44 g, 10.42 mmol) was stirred at 60°C for 1 hour. The mixture was cooled, filtered, and the filtrate was concentrated. The residue was purified by silica gel column chromatography to obtain intermediate A1-a as a light brown oil (2 g). LCMS(M+H) + ):430.

[0107] Step 2: Preparation of tert-butyl 6-[(2-amino-6-bromoanilino)methyl]-1,4-oxazepane-4-carboxylate (intermediate A1-b) Nickel (273 mg, 4.65 mmol), MeOH (20 mL), and tert-butyl 6-[(2-bromo-6-nitro-anilino)methyl]-1,4-oxazepane-4-carboxylate (intermediate A1-a, 2 g, 4.65 mmol) were added to a flask, and the suspension was vigorously stirred. Then, hydrazine (2.98 g, 2.9 mL, 46.48 mmol) was added dropwise under an ice bath. After stirring at room temperature for 3 hours, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in DCM and washed with water and brine. The organic layer was dried and concentrated to obtain intermediate A1-b as a light brown oil (1.8 g). LCMS(M+H + ): 400.

[0108] Step 3: Preparation of tert-butyl 6-[(7-bromobenzimidazole-1-yl)methyl]-1,4-oxazepan-4-carboxylate (intermediate A1-c) A mixture of tert-butyl 6-[(2-amino-6-bromoanilino)methyl]-1,4-oxazepan-4-carboxylate (intermediate A1-b, 1.8 g, 4.5 mmol) and p-toluenesulfonic acid monohydrate (86 mg, 0.45 mmol) in trimethyl orthoformate (19.4 g, 20 mL, 182.81 mmol, as the "solvent" in Table 1) was stirred at 60°C for 30 minutes. The mixture was then concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate A1-c as a pale yellow oily substance (1 g). LCMS(M+H) + ):410.

[0109] Step 4: Preparation of tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]methyl]-1,4-oxazepan-4-carboxylate (intermediate A1) To a tube, tert-butyl 6-[(7-bromobenzimidazole-1-yl)methyl]-1,4-oxazepan-4-carboxylate (intermediate A1-c, 1.1 g, 2.68 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (1.36 g, 5.36 mmol), potassium acetate (526 mg, 5.36 mmol), and DMSO (12 mL) were added. The solution was bubbling with N2 for 5 minutes, and then butyldi-1-adamantylphosphine (192 mg, 0.54 mmol) and bis(triphenylphosphine)palladium(II) dichloride (88 mg, 0.27 mmol) were added. The tube was sealed and heated at 130°C for 4 hours. The mixture was diluted with water and then extracted with EA. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain intermediate A1 (1 g) as a light brown oily substance. LCMS(M+H + ):458.

[0110] The following intermediates in Table 1 were prepared in the same manner as intermediate A1, by replacing 1-bromo-2-fluoro-3-nitrobenzene with "aryl fluoride" and tert-butyl N-(3-aminopropyl)carbamate with "amine" in step 1, and trimethyl orthoformate with "solvent" in step 3, using the reagents shown in Table 1. [Table 1] TIFF2026522985000059.tif247169 TIFF2026522985000060.tif35169

[0111] Intermediates B1 and B2 O1-tert-butylO2-methyl(2S,4S)-4-[(4-chloropyrimidine-2-yl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B1) and O1-tert-butylO2-methyl(2S,4S)-4-[(2-chloropyrimidine-4-yl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B2) [ka] The title compound was prepared according to the following scheme. [ka]

[0112] A mixture of 2,4-dichloropyrimidine (19.21 g, 128.94 mmol), 1-(tert-butyl)2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (21 g, 85.96 mmol), and K2CO3 (35.64 g, 257.89 mmol) in DMF (100 mL) was stirred at 80°C for 16 hours. The reaction mixture was then diluted with SiO2, washed with water and brine, the organic layer was concentrated, and the residue was purified by silica gel column chromatography (eluting with 10%-30% PE in SiO2). Intermediate B1 (rapid elution, 5 g) was extracted, and LCMS (M+H2) was used to obtain intermediate B1. + ):357 and intermediate B2 (slow elution, 25g), LCMS (M+H + ): 357 was obtained.

[0113] Intermediates B6 and B7 O1-benzyl O2-methyl(2S,4S)-4-[(4-chloropyrimidine-2-yl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B6) and O1-benzyl O2-methyl(2S,4S)-4-[(2-chloropyrimidine-4-yl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B7) [ka] The title compound was prepared according to the following scheme. [ka]

[0114] A mixture of 2,4-dichloropyrimidine (5.35 g, 35.9 mmol), 1-benzyl 2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (5 g, 18 mmol), K2CO3 (4.97 g, 35.9 mmol), and DIPEA (4.64 g, 35.9 mmol) in MeCN was stirred at room temperature for 48 hours. The reaction mixture was then filtered, concentrated, and the residue was purified by silica gel column chromatography (eluting with 10%-30% PE in toluene) to obtain intermediate B6 (rapid elution, 1 g). LCMS (M+H) was then used for elution. + ):391; and intermediate B7 (slow elution, 6g), LCMS (M+H + ):391.

[0115] Intermediate B8 O1-tert-butylO2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0116] A mixture of DMSO (140 mL) containing 1-(tert-butyl)2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (28.0 g, 99.7 mmol), DIPEA (69.5 mL, 398.9 mmol), and 2-bromo-6-fluoropyridine (21.1 g, 119.7 mmol) was heated at 110°C for 16 hours. The mixture was diluted with water, extracted with EA, and the organic layer was concentrated to obtain intermediate B8 (34 g). LCMS(M+H) + ): 400.

[0117] Intermediate B9 O1-tert-butylO2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)-tert-butoxycarbonyl-amino]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0118] A mixture of intermediate B8 (12.0 g, 30 mmol), 4-dimethylaminopyridine (0.73 g, 6 mmol), di-t-butyl dicarbonate (19.63 g, 89.94 mmol), and triethylamine (10.45 mL, 74.95 mmol) in DCM (60 mL) was stirred at 40°C for 16 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain intermediate B9 (11.8 g). LCMS(M+H) was used for HPLC. + ): 500.

[0119] Intermediate B10 O1-Benzyl O2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate [ka] The title compound was prepared according to the following scheme. [ka]

[0120] A mixture of O1-benzyl O2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate; hydrochloride (4.7 g, 14.93 mmol), 2-bromo-6-fluoropyridine (3.15 g, 17.92 mmol), and DIPEA (13.0 mL, 74.66 mmol) in DMSO (20 mL) was stirred at 110 °C for 16 hours. The mixture was concentrated, and the residue was purified by preparative HPLC to obtain intermediate B10 (5.1 g), LCMS(M+H+):434.

[0121] Intermediate C2 4-Chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0122] Step 1: Preparation of N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b) A mixture in DCM (400 mL) containing 4,6-dichloro-5-pyrimidine carbolide (compound C2-a, 20.0 g, 113 mmol), 2,4-difluorophenylhydrazine hydrochloride (24.9 g, 137.9 mmol), and potassium carbonate (21.2 g, 153.2 mmol) was stirred at 20°C for 12 hours. The mixture was then washed with water and brine, the organic layer was dried, and concentrated to obtain crude compound C2-b (34.5 g). LCMS(M+H) + :303.

[0123] Step 2: Preparation of 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2) A 4Å molecular sieve (2 g) was added to a solution of NMP (185 mL) containing N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-2,4-difluoroaniline (compound C2-b, 18.5 g, 61.04 mmol). The mixture was stirred at 110°C for 40 hours. The reaction mixture was cooled, and 300 mL of water was added to the reaction mixture within 20 minutes. The precipitate was collected and dried to obtain intermediate C2 (8.5 g). LC-MS (M+H) + :267.

[0124] Intermediate C3 4,6-Dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared in the same manner as the preparation of intermediate C2 by using 2,4,6-trichloropyrimidine-5-carboaldehyde instead of 4,6-dichloro-5-pyrimidinecarboaldehyde. LCMS(M+H + ):301.

[0125] Intermediate C4 4,6-Dichloro-1-(4-Fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared in the same manner as the preparation of intermediate C2, by using 2,4,6-trichloropyrimidine-5-carbaldehyde instead of 4,6-dichloropyrimidine-5-carbaldehyde and compound C11-d instead of compound C2-a. LCMS(M+H + ):313.

[0126] Intermediate C5 4,6-Dichloro-1-[4-Fluoro-2-(triduteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0127] Step 1: Preparation of 2-(4,6-dichloropyrazolo[3,4-d]pyrimidine-1-yl)-5-fluorophenol (compound C5-a) To a solution of intermediate C4 (2.0 g, 6.39 mmol) in DCM (40 mL), BCl3 / THF (31.94 mL, 31.94 mmol) was added at -78°C, and the mixture was then stirred at 25°C for 12 hours. The reaction mixture was poured into ice water (100 mL) and then extracted with DCM. The organic layer was dried and concentrated to obtain compound C5-a (1.51 g), LCMS(M+H). + ):299.

[0128] Step 2: Preparation of 4,6-dichloro-1-[4-fluoro-2-(triduteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidine (intermediate C5) A mixture of compound C5-a (1 g, 3.34 mmol), triduterio(duuteriooxy)methane (350 mg, 10.92 mmol), and PPh3 (1.3 g, 5 mmol) in toluene (15 mL) was mixed with DEAD (873 mg, 5 mmol) under N2 at 0°C, and the mixture was then stirred under N2 at 50°C for 1 hour. The reaction product was quenched with water (100 mL) and extracted with ethyl acetate. The organic layer was dried and concentrated, and the residue was purified to intermediate C5 (800 mg) by column chromatography. LCMS(M+H + ):316.

[0129] Intermediate C11 4-Chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0130] Step 1: Preparation of N-(benzhydrideneamino)-4-fluoro-2-methoxyaniline (compound C11-c) A solution of 2-bromo-5-fluoroanisole (compound C11-a, 10.0 g, 48.78 mmol), benzophenone hydrazone (compound C11-b, 10.0 g, 50.96 mmol), palladium(II) acetate (200.0 mg, 0.89 mmol), xanthophos (400.0 mg, 0.69 mmol), and sodium tert-butoxide (6.7 g, 69.72 mmol) in anhydrous toluene (150.0 mL) was stirred at 100°C for 12 hours under N2. The mixture was diluted with ELISA and washed with water and brine. The organic layer was dried and concentrated to obtain the crude product, which was recrystallized in PE (200 mL) to obtain compound C11-c (12 g), which was used directly in the next step. LCMS(M+H) + :321.

[0131] Step 2: Preparation of (4-fluoro-2-methoxyphenyl)hydrazine hydrochloride (compound C11-d) Compound C11-c (11.0 g, 34.34 mmol) and concentrated HCl (10.0 mL, 120 mmol) in ethanol (100.0 mL) were stirred at 60°C for 12 hours. The mixture was concentrated, and then SiO (100 mL) was added. After stirring for 5 minutes, the mixture was filtered, the filter cake was washed with PE (50 mL), and dried to obtain compound C11-d (4.5 g), which was used directly in the next step. LCMS(M+H) + :141.

[0132] Step 3: Preparation of N-[(4,6-dichloropyrimidine-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C11-f) A mixture of compound C11-d (4.3 g, 22.32 mmol), 4,6-dichloro-5-pyrimidine carbolide (compound C11-e, 4.3 g, 24.3 mmol), and triethylamine (3.5 g, 34.59 mmol) in anhydrous THF (100.0 mL) was stirred at 20°C for 12 hours. The reaction solution was diluted with SiO (100.0 mL) and washed with water and brine. The organic layer was dried and concentrated to obtain crude compound C11-f (5.2 g), which was used directly in the next step. LCMS(M+H) + :315.

[0133] Step 4: Preparation of 4-chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (intermediate C11) A mixture of N-[(E)-(4,6-dichloropyrimidine-5-yl)methyleneamino]-4-fluoro-2-methoxyaniline (compound C11-f, 4.0 g, 12.69 mmol) and 4 Å MS (1.0 g) in anhydrous DMF (10.0 mL) was stirred at 100 °C for 12 hours. The mixture was diluted with SiO (200.0 mL) and washed with water and brine. The organic layer was dried and concentrated to obtain the crude product, which was purified by preparative TLC to obtain intermediate C11 (747 mg). LCMS(M+H) + :279.

[0134] Intermediate C12 4-Chloro-1-(4-fluoro-2-methoxyphenyl)-6-methylpyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0135] Step 1: Preparation of (4-fluoro-2-methoxyphenyl)hydrazine hydrochloride (compound C12-b) A solution of 4-fluoro-2-methoxyaniline (compound C12-a, 30.0 g, 212.55 mmol) in HCl / water (298 mL, 1488 mmol) was stirred, and a solution of NaNO2 (22.0 g, 319 mmol) in water (300 mL) was added at 0°C. After 30 minutes, a solution of tin(II) chloride dihydrate (120 g, 532 mmol) in concentrated HCl (53 mL, 637 mmol) was added dropwise to the mixture. The mixture was stirred at 15°C for 12 hours, then the pH was adjusted to 10-12 with 20% sodium hydroxide aqueous solution, and the mixture was extracted with EA. The organic phase was dried and concentrated. The residue was acidified to pH 3-4 with HCl in dioxane, then the solid was collected and dried to obtain compound C12-b (26 g). LCMS(M+H) + :157.

[0136] Step 2: Preparation of (5-amino-1-(4-fluoro-2-methoxyphenyl)pyrazole-4-carbonitrile (compound C12-c)) To a solution of (4-fluoro-2-methoxyphenyl)hydrazine hydrochloride (compound C12-b, 11.5 g, 59.7 mmol) in ethanol (10 mL), ethoxymethylene malononitrile (7.29 g, 59.7 mmol) and DIEA (32 mL, 180 mmol) were added. The mixture was stirred at 80°C for 12 hours. The reaction mixture was concentrated, and the residue was diluted with EA. The organic layer was washed with water and brine (100 mL), concentrated, and the residue was purified by column chromatography to obtain compound C12-c (5.2 g). LCMS(M+H) + :233.

[0137] Step 3: Preparation of (N-[4-cyano-2-(4-fluoro-2-methoxyphenyl)pyrazole-3-yl]acetamide (compound C12-d) A solution of 5-amino-1-(4-fluoro-2-methoxyphenyl)pyrazole-4-carbonitrile (compound C12-c, 5.2 g, 22.39 mmol) in acetic anhydride (2.29 g, 22.39 mmol) was stirred at 100°C for 12 hours. The reaction mixture was quenched with aqueous NaOH solution (1 M, 30 mL) at 0-20°C, and then stirred at 100°C for 1 hour. The reaction mixture was diluted with water, extracted with EA, the organic layer was concentrated, and the residue was recrystallized (PE:EA = 3:1) to obtain compound C12-d (3.9 g). LC-MS (M + H) + :275.

[0138] Step 4: Preparation of 1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-ol (compound C12-e) To a solution of N-[4-cyano-2-(4-fluoro-2-methoxyphenyl)pyrazole-3-yl]acetamide (compound C12-d, 1.3 g, 4.74 mmol) in acetic acid (13 mL), phosphorus oxychloride (1.3 mL, 13.95 mmol) was added, and the reaction mixture was stirred at 110 °C for 2 hours. The reaction mixture was poured into water (100 mL), the solid was collected, and dried to obtain compound C12-e (1.1 g). LC-MS(M+H) + :275.

[0139] Step 5: Preparation of 4-chloro-1-(4-fluoro-2-methoxyphenyl)-6-methylpyrazolo[3,4-d]pyrimidine (intermediate C12) A mixture of 1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-ol (compound C12-e, 1.1 g, 4 mmol) in phosphorus oxychloride (11 mL) was stirred at 100°C for 12 hours. The reaction mixture was slowly added to an ice NaHCO3 solution and then extracted twice with DCM (50 mL). The organic layer was dried and concentrated to obtain intermediate C12 (1.1 g). LCMS(M+H) + :293.

[0140] Intermediate C17 4-Chloro-1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0141] Step 1: Preparation of 2-(cyclopropoxy)-4-fluoro-1-nitrobenzene (compound C17-a) A mixture of 2,4-difluoro-1-nitrobenzene (10.0 g, 62.86 mmol), cyclopropanol (5.0 g, 86.09 mmol), and sodium tert-butoxide (12.1 g, 0.12 mol) in THF (0.2 L) was stirred at 50°C for 1 hour. The mixture was poured into water (0.2 L) and extracted with ethyl acetate (0.2 L twice). The combined organic layer was washed with brine, dried, and concentrated. The residue was purified by silica gel column chromatography to obtain compound C17-a (8.0 g).

[0142] Steps 2-6: Preparation of 4-chloro-1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine (intermediate C17) The title compound was prepared by using compound C17-a instead of compound C18-a, similar to the preparation of intermediate C18. LC-MS(M+H) + :305.

[0143] Intermediate C18 4-Chloro-1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0144] Step 1: Preparation of 2-ethoxy-4-fluoro-1-nitrobenzene (compound C18-a) A mixture of 5-fluoro-2-nitrophenol (1.0 g, 6.4 mmol), potassium carbonate (1.7 g, 12.7 mmol), and iodoethane (0.6 mL, 7.64 mmol, 1.2 equivalents) in DMF (10.0 mL) was stirred at 30°C for 2 hours. The mixture was poured into water and extracted with butyl. The organic layer was dried and concentrated to obtain compound C18-a (1.0 g).

[0145] Step 2: Preparation of 2-ethoxy-4-fluoroaniline (compound C18-b) A mixture of 2-ethoxy-4-fluoro-1-nitrobenzene (compound C18-a, 1.0 g, 5.4 mmol) in methanol (10.0 mL) was mixed with Pd / C (0.1 g), and the mixture was stirred at 20°C for 4 hours under an H2 atmosphere. The mixture was poured into water (20.0 mL) and extracted with ELISA (twice with 20.0 mL). The organic layer was concentrated, and the residue was purified by flash chromatography column chromatography to obtain compound C18-b (0.8 g). LCMS(M+H + ):156.

[0146] Step 3: Preparation of 4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidine-5-carbaldehyde (compound C18-c) To a mixture of chloroform (20.0 mL) containing 4,6-dichloropyrimidine-5-carbaldehyde (0.8 g, 4.51 mmol) and TEA (0.9 g, 9.0 mmol), 2-ethoxy-4-fluoroaniline (compound C18-b, 0.7 g, 4.5 mmol) was added dropwise, and the mixture was stirred at 0°C for 1 hour. After washing with water, the organic layer was concentrated, and the residue was purified by silica gel column chromatography to obtain compound C18-c (0.1 g). LCMS(M+H) + ):296.

[0147] Step 4: Preparation of [[4-chloro-6-(2-ethoxy-4-fluoro-anilino)pyrimidine-5-yl]methyleneamino]bisulfate (compound C18-d) A mixture of MeCN (5.0 mL) containing aminosulfate (0.2 g, 1.7 mmol) and 4-chloro-6-(2-ethoxy-4-fluoroanilino)pyrimidine-5-carbaldehyde (compound C18-c, 0.1 g, 0.34 mmol) was stirred at 20°C for 16 hours. The mixture was used directly in the next step: LCMS(M+H + ):311.

[0148] Step 5: Preparation of 1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C18-e) A mixture of compound C18-d (0.1 g, 0.3 mmol) in ACN (5.0 mL) was mixed with NaOH aqueous solution (2.0 mL, 1 M), and the reaction mixture was stirred under N2 at 25°C for 2 hours. The mixture was purified by preparative HPLC to obtain compound C18-e (30.0 mg). LCMS(M+H) + ):275.

[0149] Step 6: Preparation of 4-chloro-1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine (compound C18-f) A solution of 1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C18-e, 20.0 mg, 0.07 mmol) in POCl3 (1.0 mL) was stirred at 100°C for 1 hour. The mixture was concentrated to obtain intermediate C18 (20.0 mg). LCMS(M+H) + ):293.

[0150] Intermediate C19 4-Chloro-1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0151] Step 1: Preparation of 2-(difluoromethoxy)-4-fluoro-1-nitrobenzene (C19-a) To a solution of 5-fluoro-2-nitrophenol (5.0 g, 31.83 mmol) and sodium chlorodifluoroacetate (5.8 g, 38.2 mmol) in DMF (60.0 mL), Na2CO3 (6.75 g, 63.65 mmol) was added. The mixture was stirred at 100°C for 2 hours, and then poured into water (200.0 mL). The resulting mixture was extracted with RINKAN, the organic layer was washed with brine, dried, and concentrated to obtain compound C19-a (5.0 g).

[0152] Steps 2-6: Preparation of 4-chloro-1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine (intermediate C19) The title compound was prepared in the same manner as the intermediate C18 by using compound C19-a instead of compound C18-a. LC-MS(M+H) + :315.

[0153] Intermediate C28 [4-Chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-6-yl]amine [ka] The title compound was prepared according to the following scheme. [ka]

[0154] Step 1: Preparation of ethyl 5-amino-1-(2,4-difluorophenyl)pyrazole-4-carboxylate (compound C28-a) A solution of 2-cyano-3-ethoxyacrylate ethyl ester (1.87 g, 11.1 mmol), (2,4-difluorophenyl)hydrazine hydrochloride (2 g, 11.1 mmol), and Et3N (3.1 mL, 22.2 mmol) in ethanol (40 mL) was stirred at 90°C for 12 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to obtain compound C28-a (2.53 g) as a pale yellow solid. LCMS(M+H) + :268.

[0155] Step 2: Preparation of 1-(2,4-difluorophenyl)-6-(methoxymethyl)-5H-pyrazolo[3,4-d]pyrimidine-4-one (compound C28-b) A mixture of compound C28-a (700 mg, 2.62 mmol) and 2-methoxyacetonitrile (372 mg, 5.24 mmol) in 4 M HCl and dioxane (8 mL) was stirred at 100°C for 14 hours. The solvent was then removed under vacuum, and the residue was partitioned between DCM and water. The organic layer was separated and concentrated, and the residue was purified by silica gel column chromatography to obtain compound C28-b (200 mg) as a light brown solid. LCMS(M+H) + :293.

[0156] Step 3: Preparation of [4-chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-6-yl]amine (intermediate C28) A suspension of compound C28-c (200 mg, 0.68 mmol) in phosphorus oxychloride (2 mL) was stirred at 90°C for 0.5 hours. The reaction mixture was then concentrated to obtain an oily substance, which was purified by silica gel column chromatography to obtain intermediate C28 (104 mg) as a white solid. LCMS(M+H) + ):311.

[0157] Intermediate C61 4-Chloro-1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine [ka] The title compound was prepared according to the following scheme. [ka]

[0158] Step 1: Preparation of 1,5-difluoro-3-methoxy-2-nitrobenzene (compound C61-b) A mixture of 3,5-difluoro-2-nitrophenol (compound C61-a, 9.5 g, 54.3 mmol), iodomethane (10.0 g, 70.5 mmol), and potassium carbonate (10.0 g, 72.4 mmol) in anhydrous DMF (250 mL) was stirred at room temperature for 12 hours. The mixture was diluted with ELISA (500 mL) and washed with water (200 mL) and brine (200 mL). The organic layer was dried and concentrated to obtain the crude product, which was purified by flash chromatography to obtain compound C61-b (10.0 g). LC-MS (M+H) + :190.

[0159] Step 2: Preparation of 2,4-difluoro-6-methoxyaniline (compound C61-c) To a mixture of 1,5-difluoro-3-methoxy-2-nitrobenzene (compound C61-b, 10.0 g, 52.9 mmol) and anhydrous siRNA (200 mL), Pd / C (1.0 g) was added, and the reaction mixture was stirred under hydrogen at room temperature for 12 hours. The mixture was filtered, and the filtrate was concentrated to obtain compound C61-c (7.5 g). LC-MS (M+H) + :160.

[0160] Steps 3-5: Preparation of 1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C61-f) Compound C61-f was prepared by using 2,4-difluoro-6-methoxyaniline instead of 2-bromo-4-fluoroaniline, similar to the preparation of intermediate C43. LC-MS(M+H) + :279.

[0161] Step 6: Preparation of 4-chloro-1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (intermediate C61) A mixture of 1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C61-f, 4.6 g, 16.5 mmol) in POCl3 (18 mL) was stirred at 100°C for 2 hours. The mixture was concentrated, the residue was dissolved in SiO4 (100 mL), and poured into an aqueous solution of NaHCO3 (100 mL). The separated organic layer was washed with brine, dried, and concentrated to obtain intermediate C61 (4.14 g). LCMS(M+H) + :297.

[0162] Intermediate C80 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-ol [ka] The title compound was prepared according to the following scheme: [ka]

[0163] Step 1: Preparation of 4-benzyloxy-6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (compound C80-a) A mixture of 4,6-dichloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C3, 1 g, 3.3 mmol), KOtBu (447 mg, 4 mmol), and benzyl alcohol (395 mg, 3.6 mmol) in tetrahydrofuran (15 mL) was stirred at room temperature for 2 hours. The reaction mixture was then diluted with EA, washed with water and brine, the organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound C80-a (400 mg). LCMS(M+H+ ):373.

[0164] Step 2: Preparation of tert-butyl 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (compound C80-b) To a solution of compound C80-a (1.25 g, 3.35 mmol) and tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate (731.32 mg, 3.69 mmol) in DMSO (20 mL), N,N-diisopropylethylamine (1.75 mL, 10 mmol) was added, and the mixture was stirred at 100°C for 1 hour. The reaction mixture was poured into water (300 mL) and extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound C80-b (2.0 g) as a brown oily substance. LCMS(M+H) + ):535.

[0165] Step 3: Preparation of 6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C80-c) To a solution of compound C80-b (4.0 g, 7.48 mmol) in DCM (20 mL), TFA was added at 0°C, and the mixture was then stirred at 25°C for 2 hours. The reaction mixture was concentrated, the residue was diluted with water (50 mL), and the mixture was freeze-dried to obtain compound C80-c (2.5 g) as a yellow solid. LCMS(M+H) + ):345. Step 4: Preparation of 1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-ol (intermediate C80)

[0166] To a solution of compound C80-b (500.0 mg, 1.09 mmol) and 1-fluoro-2-iodoethane (1.90 g, 10.91 mmol) in ACN (20 mL), triethylamine (1.5 mL, 10.91 mmol) was added, and the mixture was stirred at 80°C for 12 hours. The reaction product was quenched with water (200 mL), and the mixture was extracted with ethyl acetate (300 mL). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated. The residue was purified by reverse-phase flash column chromatography to obtain intermediate C80 (300.0 mg) as a yellow solid. LCMS(M+H) + ):391.

[0167] Intermediate C81 6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol [ka] Intermediate C81 was prepared in the same manner as intermediate C80, by using 2,2-difluoroethylmethanesulfonate instead of 1-fluoro-2-iodoethane. LCMS(M+H + ):409.

[0168] Intermediate C83 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-ol [ka] Intermediate C83 was prepared using the same method as for intermediate C80, but with tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate instead of tert-butyl3,6-diazabicyclo[3.1.1]heptane-3-carboxylate. LCMS(M+H + ):391.

[0169] Intermediate C88 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-ol [ka] The title compound was prepared according to the following scheme. [ka]

[0170] Step 1: Preparation of tert-butyl(1R,4R)-5-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (compound C88-a) To a solution of compound C80-a (1.0 g, 2.68 mmol) and tert-butyl (1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate (585 mg, 2.95 mmol) in DMSO (16 mL), N,N-diisopropylethylamine (1.4 mL, 8.05 mmol) was added, and the mixture was stirred at 90°C for 1 hour. The reaction mixture was poured into water (400 mL) and extracted with ethyl acetate (100 ml x 3). The organic layer was washed with brine (100 mL), dried over anhydrous Na2SO4, and concentrated to obtain compound C88-a (3.5 g) as a brown oily substance. LCMS(M+H) + ):535.

[0171] Step 2: Preparation of 6-[(1R,4R)-2,5-diazabicyclo[2.2.1]heptan-2-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-ol (compound C88-b) To a solution of compound C88-a (650 mg, 1.22 mmol) in DCM (10 mL), TFA (3.04 mL, 12.16 mmol) was added at 0°C, and the mixture was then stirred at 25°C for 1 hour. The reaction mixture was concentrated to obtain compound c88-b (1500 mg) as a yellow oily substance. LCMS(M+H) + ):345.

[0172] Step 3: Preparation of 1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-ol (intermediate C88) To a solution of compound C88-b (450.0 mg, 0.98 mmol) and 3-oxetanone (720.0 mg, 9.99 mmol) in DCE (9 mL), sodium triacetoxyborohydride (1.04 g, 4.91 mmol) was added at 0°C, and the mixture was stirred at 25°C for 1 hour. The mixture was diluted with H2O (30 mL) and extracted with EA (20 mL x 2). The combined organic layer was washed with brine (20 mL), dried over Na2SO4, filtered, and concentrated to obtain intermediate C88 (200.0) as a brown solid. LCMS(M+H + ):401.

[0173] Intermediate C89 1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-ol [ka] Following the preparation method for intermediate C88, intermediate C89 was synthesized using tert-butyl 3,6-diazabicyclo[3.1.1]heptane-3-carboxylate instead of tert-butyl(1R,4R)-2,5-diazabicyclo[2.2.1]heptane-2-carboxylate. LCMS(M+H + ):401.

[0174] Intermediate C90 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] The title compound was prepared according to the following scheme. [ka]

[0175] Step 1: Preparation of tert-butyl 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound C90-a) To a stirred mixture of tert-butyl 2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (1.3 g, 6.1 mmol) in THF (20 mL), sodium hydride (441 mg, 18.3 mmol) was added in fractional amounts at 0°C under a nitrogen atmosphere. After 0.5 hours, iodomethane (1.82 g, 12.8 mmol) in THF (5 mL) was added dropwise at 0°C under a nitrogen atmosphere. The resulting mixture was stirred at 25°C for 1 hour, and then the reaction solution was directly purified by reverse-phase flash column to obtain compound C90-a (1.3 g) as a white solid. LCMS(M+H + ):227.

[0176] Step 2: Preparation of 3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound C90-b) A mixture of compound C90-a (1.30 g, 5.75 mmol) in 4 M HCl (15.0 mL) in dioxane was stirred at 25°C for 2 hours. The reaction mixture was then concentrated, and the residue was freeze-dried to obtain compound C90-b (800 mg) as a yellow oily substance. LCMS(M+H) + ):127.

[0177] Step 3: Preparation of 6-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound C90-c) A mixture of compound C90-b (800 mg, 6.34 mmol), compound C80-a (1.18 g, 3.17 mmol), and DIPEA (2.50 g, 19.3 mmol) in ACN (10.0 mL) was stirred and the mixture was stirred at 80°C for 48 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to obtain compound C90-c (1.20 g) as a yellow oily substance. LCMS(M+H + ):463.

[0178] Step 4: Preparation of 6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3-methyl-3,6-diazabicyclo[3.1.1]heptan-2-one (intermediate C90) A mixture of compound C90-c (1.20 g, 2.59 mmol) in DCM (12.0 mL) and trifluoroacetic acid (12.0 mL) was stirred at 25°C for 2 hours. The reaction mixture was concentrated, and the residue was freeze-dried to obtain intermediate C90 (860 mg) as an off-white solid. LCMS(M+H) + ):373.

[0179] Intermediate C91 3-(cyclopropylmethyl)-6-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-2-one [ka] Intermediate C91 was prepared in the same manner as intermediate C90, by using bromomethylcyclopropane instead of iodomethane. LCMS(M+H + ):413.

[0180] Examples 1 and 2 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0181] Step 1: Preparation of N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propan-1-amine (1a) A mixture of tert-butyl 6-[[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]methyl]-1,4-oxazepan-4-carboxylate (intermediate A1, 1 g, 2.19 mmol, as "boron reagent" in Table 2) and HCl (4 M, 10 mL) in dioxane was stirred at room temperature for 4 hours, and the reaction product was filtered to obtain compound 1a (800 mg). LCMS(M+H) + ):358.

[0182] Step 2: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-(1,4-oxazepan-6-ylmethyl)benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b) A mixture of K2CO3 (484 mg, 3.5 mmol), N-methyl-3-[2-methyl-7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propan-1-amine (compound 1a, 469 mg, 1.3 mmol), intermediate B9 (438 mg, 0.87 mmol, as "halogen 1" in Table 2), and PdDCl2 (DPPF) (71.49 mg, 0.09 mmol) in dioxane / H2O (10:1, 10 mL) was stirred at 90°C for 2 hours. The reaction mixture was then concentrated, the residue was dissolved in THF / MeOH (7 mL, 2:1), 2 M LiOH (1.88 mL, 3.76 mmol) was added, and the mixture was stirred at room temperature for 4 hours. The reaction mixture was adjusted to pH=5, then concentrated to remove most of the organic solvent, and the residue was purified by reverse-phase flash column (MeCN / TFA in water) to obtain compound 1b (400 mg). LCMS(M+H + ):637.

[0183] Step 3: Ditert-butyl(8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaene-7,10 dicarboxylate (compound 1c) To a mixture of acetonitrile (66 mL) containing HATU (478 mg, 1.26 mmol) and DIPEA (406 mg, 3.14 mmol), acetonitrile (66 mL) containing (2S,4S)-1-tert-butoxycarbonyl-4-[tert-butoxycarbonyl-[6-[3-(1,4-oxazepan-6-ylmethyl)benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 1b, 400 mg, 0.63 mmol) was added dropwise over 2 hours. The reaction product was then concentrated, and the residue was purified by reverse-phase flash column (MeCN / TFA aqueous solution) to obtain compound 1c (100 mg). LCMS (M+H + ):619.

[0184] Step 4: (8S,11S)-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 1d) Ditert-butyl(8S,11S)-12-oxo-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] in dichloromethane (1 mL) and TFA (1 mL) 2,6 .1 8,11 .1 13,18 .0 23,27 A mixture of triaconta-1(26),2(30),3,5,21,23(27),24-heptaene-7,10-dicarboxylate (compound 1c, 100 mg, 0.16 mmol) was stirred at room temperature for 1 hour. The reaction product was concentrated to obtain compound 1d (80 mg). LCMS(M+H) + ):419.

[0185] Step 5: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .18,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Examples 1 and 2) ((8S,11S)-13,18-dimethyl-5,7,10,13,17,19,26-heptazopentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 A mixture of acetonitrile (5 mL) containing hexacosa-1(23),2,4,6(26),18,20(24),21-heptaen-12-one (compound 1d, 80 mg, 0.19 mmol), 4-chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2 as "halogen 2" in Table 2, 81.33 mg, 0.30 mmol), and DIPEA (124 mg, 0.96 mmol) was stirred at 80°C for 2 hours. The reaction product was then concentrated, and the residue was purified by HPLC to obtain Example 1 (11 mg, fast elution) and Example 2 (19 mg, slow elution).

[0186] Example 1, LCMS (M+H + ):649. 1H NMR (500MHz, methanol-d4)δ=8.60-8.34(m,1H),8.30-8.20(m,2H),7.88-7.79(m,1H),7.76-7.69(m,1H),7.69-7. 58(m,1H),7.51-7.41(m,1H),7.37-7.26(m,2H),7.23-7.15(m,1H),7.08-7.01(m,1H),6.83-6.73(m,1H),5.68- 5.49(m,2H),4.80-4.74(m,1H),4.65-4.56(m,1H),4.52-4.43(m,1H),4.38-4.30(m,2H),4.04-3.90(m,2H),3. 60-3.51(m,1H),3.39-3.33(m,1H),3.27-3.20(m,1H),3.09-3.00(m,1H),2.66-2.50(m,3H),2.20-2.03(m,1H).

[0187] Example 2, LCMS (M+H + ):649. 1 H NMR (500MHz, methanol-d4)δ=8.60-8.36(m,1H),8.25-8.07(m,1H),7.86-7.41(m,4H),7.39-7.11(m,4H),6.99-6.44(m,2 H),5.45-5.26(m,1H),4.61-4.47(m,1H),4.43-4.16(m,4H),4.14-3.52(m,8H),3.17-2.75(m,2H),2.64-2.28(m,1H).

[0188] The following examples in Table 2 were prepared in the same manner as in Examples 1 and 2, but with the reagents shown in Table 2, intermediate A1 was replaced with "boron reagent" in step 1, intermediate B1 with "halide 1" in step 2, and intermediate C2 with "halide 2" in step 5. [Table 2] TIFF2026522985000104.tif242165 TIFF2026522985000105.tif240165 TIFF2026522985000106.tif244165 TIFF2026522985000107.tif242165 TIFF2026522985000108.tif240165 TIFF2026522985000109.tif202169

[0189] Example 3 (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,18,20,28hexaazahexacyclo[16.6.1.1 2,6 .1 8,11 .1 13,16 .0 21,25 Octacosa-1(24),2(28),3,5,19,21(25),22Heptaen-12-one [ka] Example 3 was prepared in the same manner as in Example 1, by using intermediate A2 instead of intermediate A1 and intermediate B8 instead of intermediate B9. LCMS(M+H + ):619. 1 H NMR(400MHz,DMSO-d6)δ=9.58-9.50(m,1H),8.56(s,1H),8.34-8.23(m,1H),7.91-7.87(m,1H),7.78-7.67(m,1H),7.62-7.50(m,3H),7. 46-7.39(m,1H),7.36-7.28(m,1H),6.78-6.70(m,2H),6.55(d,J=8.4Hz,1H),5.06-4.98(m,1H),4.20(s,2H),4.15-4.02(m,1H),3.90(br dd,J=5.6,13.2Hz,1H),3.77(br d,J=10.4Hz,2H),3.37(br d,J=5.6Hz,2H),3.30(br d,J=12.4Hz,2H),2.87-2.75(m,1H),2.19-2.00(m,2H),1.69-1.51(m,1H).

[0190] Examples 4 and 5 (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-on [ka] [ka] The title compound was prepared according to the following scheme. [ka]

[0191] Step 1: Preparation of tert-butyl N-[trans-3-(2-bromo-6-nitroanilino)cyclopentyl]carbamate (compound 4a) Trans-cyclopentane-1,3-diamine dihydrochloride (2.99 g, 17.27 mmol), K2CO3 (5.97 g, 43.18 mmol), methanol (50 mL), and acetonitrile (50 mL) were added to a flask. The suspension was heated to 70°C, and a solution of acetonitrile (20 mL) containing 1-bromo-2-fluoro-3-nitro-benzene (1.9 g, 8.64 mmol) was added dropwise over approximately 40 minutes. The mixture was stirred for approximately 1 hour. The mixture was cooled, filtered through celite, and the collected solid was washed with ACN. The filtrate was concentrated to obtain a brown oil. The crude oil was dissolved in approximately 100 mL of EA and washed with 300 mL of saturated NH4Cl solution. The mixture was separated, and the aqueous layer was basicized with 2N aqueous NaOH solution (pH>10), and then extracted five times with 50 mL of DCM / MeOH (10:1). The DCM layer was dried over Na2SO4 and concentrated to obtain an orange oil. The oil was dissolved in dichloromethane (20 mL), and Et3N (1.12 g, 1.54 mL, 11.06 mmol) and (Boc)2O (1.81 g, 1.93 mL, 8.3 mmol) were added. The suspension was stirred at room temperature for 16 hours. The mixture was diluted with 20 mL of DCM and washed three times with 20 mL of saturated NH4Cl solution. The organic layer was dried over Na2SO4 and concentrated to obtain an orange oil. The crude oil was purified by silica gel column chromatography to obtain compound 4a (2 g). LCMS(M+H + ): 400.

[0192] Step 2: Preparation of tert-butyl N-[trans-3-(2-amino-6-bromoanilino)cyclopentyl]carbamate (compound 4b) Compound 4a (1.8 g, 4.5 mmol, 1 equivalent), aluminum-nickel alloy (577.92 mg, 6.75 mmol), and MeOH (50 mL) were added to a flask. Hydrazine hydrate (689 mg, 13.49 mmol) was then added dropwise. After 1 hour, the mixture was filtered, and the filtrate was concentrated. The residue was dissolved in EA, washed with water and brine, the organic layer was dried, and concentrated to obtain compound 4b as a crude oil (1.9 g). LCMS(M+H) + ):370.

[0193] Step 3: Preparation of tert-butyl N-[trans-3-(7-bromobenzimidazole-1-yl)cyclopentyl]carbamate (compound 4c) To a flask containing compound 4b (1.67 g, 4.5 mmol), trimethyl orthoformate (3.88 g, 4 mL, 36.56 mmol) and p-toluenesulfonic acid monohydrate (100 mg, 0.526 mmol) were added. The yellow solution was stirred at room temperature for 16 hours. The mixture was concentrated to obtain an oily substance, which was purified by silica gel column chromatography to obtain compound 4c as a yellow oily substance (1.39 g). LCMS(M+H) + ):380.

[0194] Step 4: Preparation of tert-butyl N-[trans-3-(7-bromobenzimidazole-1-yl)cyclopentyl]-N-methyl-carbamate (compound 4d) Compound 4c (1.39 g, 3.66 mmol), iodomethane (1.04 g, 457.11 μL, 7.31 mmol), and N,N-dimethylformamide (15 mL) were added to a flask. The solution was stirred at room temperature, and NaH (292.42 mg, 7.31 mmol) was added. The mixture was stirred for approximately 1 hour. The mixture was poured into 20 mL of water and extracted three times with 15 mL of EA. The organic layer was dried over Na₂SO₄ and concentrated to obtain an oily substance. This oily substance was purified by silica gel column chromatography to obtain compound 4d as a pale yellow oily substance (1.2 g). LCMS(M+H) + ):394.

[0195] Step 5: Preparation of tert-butyl N-methyl-N-[trans-3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]cyclopentyl]carbamate (compound 4e) Compound 4d (1.2 g, 3 mmol), 4,4,4',4',5,5,5',5'-octamethyl-2,2'-bi(1,3,2-dioxaborolane) (2 g, 7.88 mmol), bis(1-adamantyl)-butylphosphine (218 mg, 0.609 mmol), potassium acetate (597 mg, 6.09 mmol), and DMSO (20 mL) were added to a microwave tube. N2 was blown into the solution for 5 minutes, and bis(triphenylphosphine)palladium(ii) dichloride (213 mg, 0.304 mmol) and bis(1-adamantyl)-butylphosphine (218 mg, 0.608 mmol) were added. The tube was heated to 130°C and stirred for approximately 5 hours. The mixture was poured into 150 mL of water and then extracted twice with 30 mL of EA. The organic layer was dried and concentrated to obtain an oily substance. This oily substance was purified by silica gel column chromatography to obtain compound 4e as an oily substance (1.1 g). LCMS(M+H + ):442.

[0196] Step 6: Preparation of O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[(1S)-3-[tert-butoxycarbonyl(methyl)amino]cyclopentyl]benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 4f) Compound 4e (1.1 g, 2.49 mmol), O1-benzyl O2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate (intermediate B10, 0.90 g, 2.07 mmol), K2CO3 (689 mg, 4.98 mmol), 1,4-dioxane (8 mL), and water (0.500 mL) were added to a microwave tube. The suspension was bubbling with N2 for 5 minutes, and 1,1'-bis(diphenylphosphin)ferrocene-palladium(ii) dichloride dichloromethane complex (203 mg, 0.249 mmol) was added. After stirring at 100°C for 2 hours, the mixture was diluted with 50 mL of water and extracted three times with 30 mL of EA. The organic layer was dried over Na2SO4 and concentrated. The crude oily substance was purified by silica gel column chromatography to obtain compound 4f as a pale yellow oil (1.1 g). LCMS(M+H+ ):669.

[0197] Step 7: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[trans-3-(methylamino)cyclopentyl]benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (4g of compound) To a flask containing compound 4f (1.1 g, 1.64 mmol), tetrahydrofuran (4 mL) and methanol (4 mL) were added. The solution was stirred at room temperature, and 2 M LiOH (2N aqueous solution) (4 mL, 8 mmol) was added dropwise. The mixture was stirred for 2 hours. Then, it was diluted with 20 mL of water to adjust the pH to approximately 4, and the mixture was extracted three times with 20 mL of DCM. The organic layer was dried over Na2SO4 and concentrated to obtain a foamy solid. The solid was redissolved in dichloromethane (2 mL) and TFA (2 mL), and the mixture was stirred at room temperature for 1 hour. Then, the mixture was concentrated to obtain 4 g of compound as crude oil (approximately 890 mg). LCMS(M+H + ):555.

[0198] Step 8: Benzyl(8S,11S)-6-methyl-7-oxo-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Preparation of octacosa-13,15,17(26),18,20,22(25),23-heptaene-9-carboxylate (compound 4h) A solution of HATU (760 mg, 2 mmol) and DIEA (620 mg, 4.8 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (150 mL) was added dropwise to a separate suspension of compound 4 g (535 mg, 0.800 mmol) in N,N-dimethylformamide (2 mL) and acetonitrile (150 mL), which took approximately 2 hours. The mixture was concentrated to remove most of the ACN and DMF. The residue was purified by silica gel column chromatography and preparative HPLC to obtain compound 4h (350 mg) as a light brown oily substance. LCMS(M+H + ):537.

[0199] Step 9: (8S,11S)-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Preparation of octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one (compound 4i) Compound 4h (100 mg, 0.154 mmol), methanol (0.200 mL), and 4M aqueous HCl solution (2 mL, 8 mmol) were added to a tube. The solution was heated to 100°C and stirred for 3 hours. The mixture was directly concentrated to obtain compound 4i as a brown oily substance (90 mg). LCMS(M+H) + ):403.

[0200] Step 10: (8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Preparation of octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one (compound 4j) Compound 4i (707 mg, 1.2 mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 320 mg, 1.2 mmol), DIEA (775 mg, 6 mmol), and acetonitrile (3 mL) were added to a microwave tube. The brown solution was heated to 85°C and stirred for 2 hours. The mixture was concentrated to obtain a residue, which was purified by silica gel column chromatography to obtain compound 4j as an oily substance. LCMS(M+H + ):633.

[0201] Step 11: (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one and (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1 2,5 .1 8,11 .1 13,17 .0 22,25 Preparation of octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one (Examples 4 and 5) Compound 4i was separated by SFC to obtain Example 4 (fast elution) and Example 5 (slow elution). (SFC conditions: Instrument: SFC80; Column: Pyridine, inner diameter 250 × 30 mm, 5 μm; Mobile phase: A for CO2, B for IPA (0.1% NH3H2O), Gradient: B 35%; Flow rate: 60 mL / min; Back pressure: 100 bar; Column temperature: 35°C)

[0202] Example 4, LCMS (M+H + ):633. 1H NMR(500MHz,メタノール-d4)δ=8.51(s,1H),8.39(s,1H),8.22(s,1H),7.80(dd,J=7.4,8.3Hz,1H),7.73-7.69(m,1H),7.65(dt, J=5.8,8.6Hz,1H),7.33-7.24(m,2H),7.23-7.15(m,2H),6.94(d,J=7.3Hz,1H),6.75(d,J=8.4Hz,1H),5.60(d,J=8.7Hz,1H) ,4.73-4.69(m,1H),4.60-4.53(m,1H),4.50-4.42(m,1H),4.27-4.22(m,1H),4.22-4.16(m,1H),3.64-3.60(m,1H),3.16-3 .02(m,3H),2.59(ddd,J=4.9,8.7,13.5Hz,1H),2.52-2.46(m,1H),2.30-2.21(m,1H),2.09-1.97(m,2H),1.97-1.86(m,2H).

[0203] Example 5: LCMS(M+H) + ):633. 1 H NMR(500MHz,メタノール-d4)δ=8.52(s,1H),8.37(d,J=10.4Hz,1H),8.23(s,1H),7.83-7.77(m,1H),7.72(dd,J=1.5,7.6Hz,1H), 7.69-7.62(m,1H),7.33-7.25(m,3H),7.23-7.16(m,1H),6.94(d,J=7.5Hz,1H),6.70(d,J=8.2Hz,1H),6.01-5.82(m,1H),5. 31(d,J=9.2Hz,1H),4.67-4.57(m,1H),4.53-4.46(m,1H),4.37-4.29(m,1H),3.79-3.65(m,1H),3.13-3.00(m,3H),2.75-2. 60(m,2H),2.53-2.44(m,1H),2.43-2.37(m,1H),2.30-2.23(m,1H),1.72-1.65(m,1H),1.64-1.56(m,1H),1.55-1.48(m,1H).

[0204] Example 8 (8S,11S)-10-[1-(4-fluoro-2-methoxy-phenyl)pyrazolo[3,4-d]pyrimidin-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0205] Steps 1-6: Preparation of O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[[3-[[tert-butoxycarbonyl(methyl)amino]methyl]oxetane-3-yl]methyl]-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 8f) Compound 8f was prepared in the same manner as the preparation of O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[(1S)-3-[tert-butoxycarbonyl(methyl)amino]cyclopentyl]benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 4f), by using [3-(aminomethyl)oxetane-3-yl]methaneamine instead of (1S,3S)-cyclopentane-1,3-diamine in Step 1, and 1,1,1-trimethoxyethane instead of trimethyl orthoformate in Step 3. + ):690.

[0206] Step 7: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[2-methyl-3-[[3-(methylaminomethyl)oxetane-3-yl]methyl]benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (8g) To a flask containing compound 8f (500 mg, 0.716 mmol), tetrahydrofuran (4 mL) and methanol (2 mL) were added. The solution was stirred at room temperature, and LiOH (2N aqueous solution) (2 mL, 4 mmol) was added dropwise. The mixture was stirred for 2 hours, diluted with 20 mL of water, and the pH was adjusted to approximately 6 with 1N aqueous HCl. Then, it was extracted three times with 10 mL of DCM / MeOH (9:1). The organic layer was dried over Na2SO4 and concentrated to obtain a foamy solid (500 mg). To a flask containing the crude solid (500 mg, 0.73 mmol), formic acid (10.8 g, 9 mL) and water (1 mL) were added. The brown solution was stirred at room temperature for 16 hours, and the mixture was concentrated (25°C) to obtain a brown oily substance, which was purified by preparative HPLC to obtain 8 g of the compound as a white powder (300 mg). LCMS(M+H) + ):585.

[0207] Step 8: Benzyl(8S,11S)-13,18-dimethyl-12-oxospiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-10-carboxylate (8h) To a solution of HATU (408 mg, 1.07 mmol) and DIEA (333 mg, 2.58 mmol) in acetonitrile (75 mL), 8 g (300 mg, 0.429 mmol) of compound in acetonitrile (75 mL) was added dropwise over approximately 2 hours. The mixture was then concentrated, and the residue was purified by preparative HPLC to obtain compound 8h as a light brown oily substance (120 mg). LCMS(M+H) + ):567.

[0208] Step 9: (8S,11S)-13,18-dimethylspiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one (8i) To a flask containing compound 8h (120 mg, 0.211 mmol), methanol (50 mL) and palladium hydroxide (50% H2O) (20% carbon) (30 mg, 0.214 mmol) were added. The suspension was purged three times with H2. The mixture was heated at 65°C for 1.5 hours, filtered, and the filtrate was concentrated to obtain compound 8i as an oily substance (107 mg).

[0209] Step 10: (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one (Example 8) Compound 8i (54 mg, 0.125 mmol), DIEA (48 mg, 0.375 mmol), acetonitrile (2 mL), and 4-chloro-1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine (intermediate C11, 35 mg, 0.125 mmol) were added to a microwave tube. The solution was heated to 85°C for about 1 hour, then the mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 8 as a white powder. LCMS(M+H) + ):675. 1H NMR (500MHz, methanol-d4)δ=8.52-8.34(m,1H),8.27(s,1H),8.12(d,J=8.2Hz,1H),7.93(dd,J=7.6,8.2Hz,1H),7.75(dd,J=1.0,8.0Hz,1H) ,7.45-7.33(m,3H),7.26(d,J=7.2Hz,1H),7.05(dd,J=2.4,10.7Hz,1H),6.91-6.82(m,1H),5.67-5.37(m,2H),4.37-4.25(m,1H),4.18(br d,J=6.6Hz,1H),4.08(br d,J=6.4Hz,1H),4.05-3.99(m,1H),3.95-3.86(m,1H),3.84-3.76(m,1H),3.75(s,3H),3 .30-3.30(m,3H),2.68(s,3H),2.56-2.38(m,2H),2.38-2.19(m,2H),2.03-1.72(m,2H).

[0210] Examples 21 and 22 (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 22) [ka] The title compound was prepared according to the following scheme. [ka]

[0211] Steps 1-3: Benzyl(8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound 21c) Compound 21c was prepared in the same manner as compound 1c, by using intermediate A6 instead of intermediate A1 and intermediate B10 instead of intermediate B9. LCMS(M+H + ):585.

[0212] Step 4: (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 21d) Benzyl(8S,11S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1] in TFA (20 mL) 2,6 .1 8,11 .1 13,18 .0 23,27A mixture of triaconta-1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound 21c, 3g, 5.13 mmol) was stirred at 95°C for 2 hours. The reaction product was then concentrated and purified by reverse-phase flash column (MeCN / 0.5% TFA aqueous solution) to obtain compound 21d (80 mg). LCMS (M+H + ):451.

[0213] Step 5: (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 21) and (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 22) (8S,11S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 21d, 80 mg, 0.18 mmol), intermediate C19 (56 mg, 0.18 mmol), and DIPEA (115 mg, 0.89 mmol) were mixed in acetonitrile (5 mL) and stirred at 80°C for 2 hours. The reaction product was then concentrated, and the residue was purified by HPLC to obtain Example 21 (10 mg, fast elution) and Example 22 (10 mg, slow elution).

[0214] Example 21, LCMS (M+H + ):729. 1 H NMR (500MHz, methanol-d4) δ=8.61-8.31(m,1H),8.25-7.76(m,2H),7.70-7.53(m,1H),7.40-7. 14(m,4H),7.10-6.65(m,3H),6.13-5.93(m,1H),5.67-5.42(m,1H),4.78-4.69(m,1H),4.64- 4.55(m,1H),4.41-4.26(m,2H),4.23-3.96(m,2H),3.94-3.82(m,1H),3.51-3.38(m,2H),3. 31-3.05(m,2H),2.99-2.74(m,1H),2.73-2.48(m,4H),1.64-1.51(m,1H),1.32-1.18(m,1H).

[0215] Example 22, LCMS (M+H + ):729. 1 ¹H NMR (500MHz, methanol-d4) δ = 8.61-8.32 (m,1H), 8.26-8.13 (m,1H), 7.72-7.57 (m,1H), 7.52-7.41 (m,1H), 7.33-7.17 (m,3H), 7.09-6.39 (m,4H), 5.41-5.21 (m,1H), 4.63- 4.39(m,2H),4.28-4.05(m,2H),4.00-3.80(m,4H),3.76-3.47(m,2H),3.42-3.35( m,1H),3.16-2.88(m,2H),2.65-2.43(m,4H),2.11-1.92(m,1H),1.92-1.74(m,1H).

[0216] Examples 23 and 24 (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 23) and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 24) [ka] [ka] Examples 23 and 24 were prepared in the same manner as the preparations for Examples 21 and 22, but by using intermediate C17 instead of intermediate C19.

[0217] Example 23, Rapid elution, LCMS(M+H + ):719. 1H NMR (500MHz, methanol-d4)δ=8.57-8.26(m,1H),8.20-7.74(m,2H),7.51-7.27(m,3H),7.22-7.13(m,1H),7.03-6.96(m,1H) ,6.96-6.87(m,1H),6.77-6.62(m,1H),6.10-5.89(m,1H),5.63-5.41(m,1H),4.79-4.70(m,1H),4.63-4.46(m,1H),4.42- 4.27(m,2H),4.23-4.15(m,1H),4.14-3.98(m,1H),3.94-3.80(m,2H),3.51-3.37(m,2H),3.30-3.18(m,1H),3.17-3.06( m,1H),3.00-2.76(m,1H),2.70-2.48(m,4H),1.62-1.48(m,1H),1.29-1.13(m,1H),0.82-0.70(m,2H),0.67-0.53(m,2H).

[0218] Example 24, Slow elution, LCMS(M+H + ):719. 1 ¹H NMR (500MHz, methanol-d4) δ = 8.51-8.24 (m,1H), 8.20-7.74 (m,1H), 7.70-7.38 (m,2H), 7.37-7.26 (m,2H), 7.09-6.97 (m,1H), 6.96-6.40 (m,3H), 5.42-5.20 (m,1H), 4.65-4.36 (m,2H) H),4.29-4.05(m,2H),4.00-3.76(m,5H),3.74-3.54(m,2H),3.19-2.83(m,3H),2.73-2 .42(m,4H),2.15-1.93(m,1H),1.90-1.74(m,1H),0.84-0.66(m,2H),0.66-0.39(m,2H).

[0219] Examples 25 and 26 (8S,11S,18S)-10-[1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .18,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 25) and (8S,11S,18R)-10-[1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 26) [ka] [ka] Examples 25 and 26 were prepared in the same manner as the preparations for Examples 21 and 22, but by using intermediate C18 instead of intermediate C19.

[0220] Example 25, Rapid elution, LCMS(M+H + ):707. 1H NMR (500MHz, methanol-d4)δ=8.63-8.29(m,1H),8.24-7.72(m,2H),7.52-7.38(m,1H),7.34-7.26(m,1H),7.18-7. 10(m,1H),7.09-6.94(m,2H),6.91-6.84(m,1H),6.75-6.66(m,1H),6.08-5.89(m,1H),5.64-5.41(m,1H),4.77- 4.70(m,1H),4.65-4.54(m,1H),4.43-4.26(m,2H),4.25-3.96(m,4H),3.92-3.82(m,1H),3.50-3.38(m,2H),3. 30-3.04(m,2H),3.00-2.77(m,1H),2.71-2.51(m,4H),1.61-1.48(m,1H),1.35-1.22(m,1H),1.22-1.13(m,3H).

[0221] Example 26, Slow elution, LCMS(M+H + ):707. 1 H NMR (500MHz, methanol-d4) δ=8.58-8.25(m,1H),8.24-7.73(m,1H),7.56-7.38(m,2H),7.35 -7.22(m,1H),7.09-6.93(m,2H),6.94-6.45(m,3H),5.40-5.26(m,1H),4.62-4.47(m,3H ),4.27-4.11(m,2H),4.06(q,J=7.0Hz,2H),3.97-3.79(m,4H),3.71-3.60(m,2H),3.12- 2.91(m,2H),2.64-2.44(m,4H),2.11-1.97(m,1H),1.89-1.75(m,1H),1.21-1.09(m,3H).

[0222] Examples 27 and 28 (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .023,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 27) and (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 28) [ka] [ka] Examples 27 and 28 were prepared in the same manner as the preparations for Examples 21 and 22, but by using intermediate C11 instead of intermediate C19.

[0223] Example 27, Rapid elution, LCMS(M+H + ):693. 1H NMR (500MHz, methanol-d4)δ=8.58-8.30(m,1H),8.24-8.16(m,1H),7.85-7.74(m,1H),7.51-7.36(m,1H),7.33-7.25(m,1H),7.2 0-7.12(m,1H),7.11-7.04(m,1H),7.03-6.95(m,1H),6.93-6.82(m,1H),6.76-6.63(m,1H),6.12-5.90(m,1H),5.67-5.42(m,1) H),4.78-4.70(m,1H),4.64-4.55(m,1H),4.40-4.25(m,2H),4.24-3.97(m,2H),3.92-3.82(m,1H),3.81-3.72(m,3H),3.51-3 .36(m,2H),3.29-3.21(m,1H),3.17-3.06(m,1H),2.96-2.75(m,1H),2.71-2.48(m,4H),1.58-1.48(m,1H),1.34-1.15(m,1H).

[0224] Example 28, Slow elution, LCMS(M+H + ):693. 1 H NMR (500MHz, methanol-d4) δ=8.56-8.40(m,1H),8.24-8.11(m,1H),7.56-7.37(m ,2H),7.35-7.22(m,1H),7.12-6.81(m,4H),6.64-6.50(m,2H),5.41-5.24(m,1 H),4.65-4.41(m,3H),4.28-4.08(m,2H),4.04-3.81(m,5H),3.71-3.59(m,2H ),3.16-2.90(m,3H),2.66-2.42(m,5H),2.16-1.98(m,1H),1.92-1.78(m,1H).

[0225] Examples 29 and 30 (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .113,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 29) and (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 30) [ka] [ka] Examples 29 and 30 were prepared in the same manner as the preparations for Examples 21 and 22, but by using intermediate C12 instead of intermediate C19.

[0226] Example 29, Rapid elution, LCMS(M+H + ):707. 1 ¹H NMR (500MHz, methanol-d4) δ = 8.48-7.65 (m,2H), 7.50-7.35 (m,1H), 7.32-7.27 (m,1H), 7.18-7.10 (m,1H), 7.10-7.03 (m,1H), 7.03-6.97 (m,1H), 6.93-6.85 (m,1H), 6.77-6.65 (m,1H), 6.14-5.92 (m,1H), 5.67-5.43 (m,1 H),4.79-4.69(m,1H),4.63-4.50(m,1H),4.40-4.08(m,4H),4.08-3.84(m,2H),3.83-3.72(m,3H),3.49-3 .42(m,1H),3.27-3.10(m,1H),2.98-2.71(m,1H),2.70-2.37(m,8H),1.65-1.47(m,1H),1.34-1.15(m,1H).

[0227] Example 30, slow elution, LCMS(M+H + ):707. 1 H NMR (500MHz, methanol-d4) δ=8.46-8.30(m,1H),7.52-7.35(m,2H),7.33-7.25(m ,1H),7.09-6.99(m,2H),6.92-6.52(m,3H),5.37-5.15(m,1H),4.63-4.53(m,1 H),4.52-4.33(m,2H),4.25-4.03(m,2H),4.03-3.80(m,4H),3.79-3.59(m,5H ),3.13-2.88(m,2H),2.62-2.33(m,7H),2.12-1.97(m,1H),1.92-1.79(m,1H).

[0228] Examples 31 and 32 (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 31) and (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 32) [ka] Examples 31 and 32 were prepared in the same manner as the preparations for Examples 21 and 22, except that intermediate B6 was used instead of intermediate B10 in step 2 and intermediate C11 was used instead of intermediate C19 in step 5. Examples 31 and 32 were obtained by SFC separation. SFC conditions: Instrument: SFC 80, Column: GS Ethyl Pyridine II, inner diameter 50 × 20 mm, 5 μm; Mobile phase: A for CO2, B for IPA (0.1% NH3H2O), Gradient: B 35%; Flow rate: 50 mL / min; Back pressure: 100 bar; Column temperature: 35°C.

[0229] Example 31, Rapid elution, LCMS(M+H + ):694. 1 H NMR (500MHz, methanol-d4) δ=8.75-8.45(m,1H),8.42-8.07(m,2H),7.58-7.36(m ,2H),7.35-7.12(m,1H),7.11-7.01(m,1H),7.01-6.65(m,2H),5.42-5.16(m,1 H),4.79-4.44(m,3H),4.39-3.88(m,5H),3.86-3.72(m,4H),3.71-3.55(m,1H ),3.15-2.88(m,2H),2.82-2.48(m,5H),2.21-2.07(m,1H),2.02-1.81(m,1H).

[0230] Example 32, Slow elution, LCMS(M+H + ):694. 1¹H NMR (500MHz, methanol-d4) δ = 8.58-8.26 (m,2H), 8.24-7.77 (m,1H), 7.54-7.33 (m,2H), 7.30-7.19 (m,1H), 7.13-7.03 (m,1H), 7.03-6.97 (m,1H), 6.96-6.85 (m,1H), 5.92-5.73 (m,1H), 5.64-5.44 (m,1 H),4.83-4.66(m,1H),4.58-4.49(m,1H),4.42-4.11(m,4H),4.10-4.01(m,1H),3.91-3.71(m,4H ),3.53-3.37(m,3H),3.21-3.11(m,1H),3.10-2.90(m,1H),2.76-2.50(m,4H),1.68-1.49(m,1H).

[0231] Examples 37 and 38 (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 37) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30heptazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 38) [ka] [ka] Examples 37 and 38 were prepared in the same manner as the preparations for Examples 31 and 32, but by using intermediate C28 instead of intermediate C11.

[0232] Example 37, Rapid elution, LCMS(M+H + ):726. 1 ¹H NMR (500MHz, methanol-d4) δ = 8.56-7.82 (m,1H), 7.70-7.53 (m,2H), 7.46-7.36 (m,1H), 7.34-7.26 (m,1H), 7.24-7.16 (m,1H), 7.03-6.85 (m,1H), 6.76-6.56 (m,1H), 5.41-5.19 (m,1H), 4.64- 4.33(m,5H),4.30-3.81(m,5H),3.79-3.57(m,1H),3.56-3.44(m,2H),3.43-3.36(m,2H),3. 24-2.97(m,3H),2.91-2.77(m,3H),2.69-2.45(m,1H),2.20-2.07(m,1H),2.03-1.85(m,1H).

[0233] Example 38, Slow elution, LCMS(M+H + ):726. 1 ¹H NMR (500MHz, methanol-d4) δ = 8.58-7.77 (m,2H), 7.74-7.60 (m,1H), 7.60-7.47 (m,2H), 7.35-7.17 (m,2H), 7.14-7.00 (m,1H), 6.87-6.68 (m,1H), 6.44-6.24 (m,1H), 5.75-5.43 (m,1H), 4.81-4.73 (m,1 H),4.64-4.57(m,1H),4.56-4.38(m,2H),4.38-4.25(m,3H),4.19-3.96(m,2H),3.53-3.39(m,5H ),3.29-3.09(m,1H),2.98-2.75(m,4H),2.75-2.44(m,1H),1.67-1.53(m,1H),1.29-1.15(m,1H).

[0234] Example 39 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,17 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 39 was prepared in the same manner as the preparation of Example 21, by using intermediate A9 instead of intermediate A6 in step 1 and intermediate C2 instead of intermediate C19 in step 5. LCMS(M+H + ):681. 1 ¹H NMR (500MHz, methanol-d4) δ=8.54(s,1H),8.20(d,J=3.2Hz,1H),7.71-7.64(m,1H),7.64-7.55(m,2H),7.34-7.25(m,2H),7.24-7.15(m,1H),6.90(br d,J=7.0Hz,1H),6.79-6.62(m,1H),5.37(d,J=8.9Hz,1H),5.20-4.95(m ,1H),4.76-4.56(m,1H),4.50-4.35(m,2H),4.33-3.98(m,4H),3.82-3. 72(m,1H),3.21-3.06(m,1H),3.03-2.93(m,1H),2.90-2.83(m,4H),2.8 1-2.66(m,1H),2.44-2.19(m,1H),2.01-1.79(m,1H),1.61-1.25(m,1H).

[0235] Examples 40 and 41 (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .18,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 40) and (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 41) [ka] [ka] Examples 40 and 41 were prepared in the same manner as the preparations for Examples 21 and 22, but by using intermediate C61 instead of intermediate C19.

[0236] Example 40, rapid elution, LCMS(M+H + ):711. 1 H NMR (500MHz, methanol-d4)δ=8.63-8.41(m,1H),8.23-8.09(m,1H),7.64-7.48(m ,2H),7.43-7.30(m,1H),7.04-6.52(m,4H),5.40-5.24(m,1H),4.63-4.16(m,4 H),4.12-3.87(m,4H),3.85-3.74(m,3H),3.71-3.57(m,2H),3.22-2.96(m,3H ),2.89-2.77(m,3H),2.72-2.45(m,1H),2.17-2.03(m,1H),1.92-1.78(m,1H).

[0237] Example 41, Slow elution, LCMS(M+H + ):711. 1¹H NMR (500MHz, methanol-d4) δ = 8.63-8.54 (m,1H), 8.25-8.17 (m,1H), 7.90-7.82 (m,1H), 7.59-7.48 (m,2H), 7.11-7.03 (m,1H), 7.00-6.94 (m,1H), 6.91-6.84 (m,1H), 6.83-6.78 (m,1H), 6.45-6.27 (m,1H), 5.66-5.48 (m,1 H),4.80-4.75(m,1H),4.67-4.58(m,1H),4.38-4.29(m,3H),4.08-3.97(m,2H),3.85-3.74(m,4H),3.56-3 .47(m,2H),3.21-3.09(m,1H),2.97-2.78(m,4H),2.76-2.51(m,1H),1.66-1.48(m,1H),1.29-1.14(m,1H).

[0238] Examples 42 and 43 (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 43) [ka] The title compound was prepared according to the following scheme. [ka]

[0239] Step 1: (8S,11S,18R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one and (8S,11S,18S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compounds 42a-1 and 42a-2) Compounds 42a-1 and 42a-2 were prepared in the same manner as in the preparations of Examples 21 and 22, by using intermediate C3 instead of intermediate C19. LCMS(M+H + ):715.

[0240] Step 2: (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18.0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 42) and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 43) (8S,11S,18R)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one compound 42a-1 (80 mg, 0.11 mmol), 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate) (114 mg, 0.33 mmol), and DIPEA (145 mg, 1.1 mmol) were mixed in acetonitrile (5 mL) and stirred at 80°C for 24 hours. The reaction product was then concentrated, and the residue was purified by preparative HPLC to obtain Example 42 (46 mg). LCMS(M+H + ):791. 1H NMR (500MHz, methanol-d4)δ=8.74-8.18(m,1H),7.61-7.46(m,1H),7.43-7.32(m,1H), 7.21-7.01(m,3H),6.97-6.82(m,1H),6.60-6.38(m,2H),5.18-4.99(m,1H),4.46(br t,J=3.9Hz,2H),4.36-4.03(m,5H),4.01-3.84(m,2H),3.82-3.72(m,2H),3 .64-3.41(m,4H),3.03-2.78(m,3H),2.62-2.31(m,9H),1.91-1.67(m,3H).

[0241] (8S,11S,18S)-10-[6-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one compound 42a-2 (80 mg, 0.11 mmol), 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate) (114 mg, 0.33 mmol), and DIPEA (145 mg, 1.1 mmol) were mixed in acetonitrile (5 mL) and stirred at 80°C for 24 hours. The reaction product was then concentrated, and the residue was purified by preparative HPLC to obtain Example 43 (70 mg). LCMS(M+H + ):791. 1 ¹H NMR (500 MHz, methanol-d4) δ = 1H NMR (400MHz, methanol-d4)δ=8.39-7.53(m,3H),7.36-7.09(m,4H),7.05-6.91(m ,1H),6.78-6.60(m,1H),6.16-5.86(m,1H),5.55-5.37(m,1H),4.78-4.39(m,4 H),4.34-3.96(m,6H),3.94-3.81(m,1H),3.79-3.56(m,1H),3.53-3.37(m,4H ),3.28-3.01(m,2H),2.98-2.46(m,9H),1.62-1.48(m,1H),1.35-1.17(m,1H).

[0242] Example 44 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 44 was prepared in accordance with the preparation of Example 43, but using (1R,4R)-2-methyl-2,5-diazabicyclo[2.2.1]heptane (dihydrochloride) instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate). LCMS(M+H + ):791. 1¹H NMR (400MHz, methanol-d4) δ = 8.17-7.44 (m,3H), 7.22-6.97 (m,4H), 6.90-6.78 (m,1H), 6.63-6.50 (m,1H), 5.98-5.80 (m,1H), 5.45-5.25 (m,1H), 4.63-4.36 (m,3H), 4.23- 3.86(m,5H),3.84-3.43(m,3H),3.42-3.28(m,2H),3.14-2.92(m,1H),2.88-2.58( m,3H),2.56-2.28(m,8H),1.91-1.75(m,2H),1.49-1.36(m,1H),1.21-1.06(m,1H).

[0243] Example 45 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0244] Step 1: Preparation of [1-[(2-bromo-4-fluoro-6-nitro-anilino)methyl]cyclopropyl]methanol (compound 45a) DIEA (8.02 g, 75.63 mmol) was added to a mixture of 1-bromo-2,5-difluoro-3-nitrobenzene (6.0 g, 25.21 mmol) and [1-(aminomethyl)cyclopropyl]methanol (3.06 g, 30.25 mmol) in DMF (60 mL). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted twice with ethyl acetate. The combined organic layer was washed with brine, dried, and concentrated to obtain some residue. The residue was purified by flash chromatography to obtain compound 45a (7.0 g) as a yellow oil. LCMS(M+H) + ):319.

[0245] Step 2: Preparation of [1-[(2-amino-6-bromo-4-fluoro-anilino)methyl]cyclopropyl]methanol (compound 45b) [1-[(2-bromo-4-fluoro-6-nitro-anilino)methyl]cyclopropyl]methanol (compound 45a, 7.0 g, 21.93 mmol) was dissolved in ethyl acetate (100 mL), to which Pt / C (1.0 g) was added. The reaction mixture was stirred under hydrogen at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated to obtain compound 45b (6.0 g, 20.75 mmol) as a yellow oily substance. LCMS(M+H) + ):289.

[0246] Step 3: Preparation of [1-[(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)methyl]cyclopropyl]methanol (compound 45c)] A mixture of [1-[(2-amino-6-bromo-4-fluoro-anilino)methyl]cyclopropyl]methanol (compound 45b, 6.0 g, 20.75 mmol) and trimethyl orthoacetate (3.74 g, 31.13 mmol) in THF (60 mL) was mixed with pyridinium p-toluenesulfonate (1.04 g, 4.15 mmol). The reaction mixture was stirred at room temperature for 1 hour. The reaction mixture was poured into water and extracted twice with butyl. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated to obtain some residue. The residue was purified by preparative HPLC to obtain compound 45c (6.0 g) as a white solid. LCMS(M+H) + ):313.

[0247] Step 4: Preparation of 7-bromo-1-[[1-(chloromethyl)cyclopropyl]methyl]-5-fluoro-2-methyl-benzimidazole (compound 45d) A solution of [1-[(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)methyl]cyclopropyl]methanol (compound 45c, 4.0 g, 12.77 mmol) in SOCl2 (20.0 mL) was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 45d (4.2 g) as a white solid, which was used in the next step without further purification. LCMS(M+H) + ):331.

[0248] Step 5: Preparation of tert-butyl N-[[1-[(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45e) To a mixture of tert-butyl N-methylcarbamate (3.32 g, 25.33 mmol) and 7-bromo-1-[[1-(chloromethyl)cyclopropyl]methyl]-5-fluoro-2-methyl-benzimidazole (compound 45d, 4.2 g, 12.67 mmol) in DMF (40 mL), NaH (0.61 g, 15.2 mmol) was added in fractions at 0°C, and the reaction mixture was then stirred at 0°C for 1 hour. The reaction mixture was poured into a saturated NH4Cl solution and then extracted three times with RINKAN. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, concentrated and dried to obtain some residue. The residue was purified by silica gel column chromatography to obtain compound 45e (3.0 g) as a white solid. LCMS(M+H + ):426.

[0249] Step 6: Preparation of tert-butyl N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methyl-benzimidazole-1-yl]methyl]cyclopropyl]methyl]N-methyl-carbamate (compound 45f) Pd-Ad2nBuP (93.9 mg, 0.14 mmol) was added to a mixture of 1,4-dioxane (6 mL) containing tert-butyl N-[[1-[(7-bromo-5-fluoro-2-methyl-benzimidazole-1-yl)methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45e, 600.0 mg, 1.41 mmol), 6-chloropyridine-2-boronic acid pinacol ester (337 mg, 1.41 mmol), and potassium phosphate (500 mg, 4.22 mmol) and water (1 mL). The reaction mixture was stirred under nitrogen at 60°C for 1 hour. After cooling to room temperature, the reaction mixture was quenched with water and then extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated under reduced pressure to obtain some residue. The residue was purified by reverse-phase flash column chromatography, the desired fraction was concentrated under reduced pressure, and then the fraction was extracted three times with ethyl acetate. The combined organic layers were washed with brine, dried, and concentrated to obtain compound 45f (400 mg) as a yellow oil. LCMS(M+H + ):459.

[0250] Step 7: Preparation of O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]6-fluoro-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (45g of compound) A mixture of 1,4-dioxane (5 mL) containing O1-benzyl O2-methyl(2S,4S)-4-aminopyrrolidine-1,2-dicarboxylate (243 mg, 0.87 mmol), tert-butyl N-[[1-[[7-(6-chloro-2-pyridyl)-5-fluoro-2-methyl-benzimidazole-1-yl]methyl]cyclopropyl]methyl]-N-methyl-carbamate (compound 45f, 400.0 mg, 0.87 mmol), tris(dibenzylideneacetone)dipalladium(0) (159 mg, 0.17 mmol), 2-dicyclohexylphosphino-2',6'-dimethoxybiphenyl (71 mg, 0.17 mmol), and cesium carbonate (852 mg, 2.61 mmol) was stirred at 100°C for 12 hours under nitrogen. After cooling to room temperature, the reaction mixture was poured into water and extracted twice with dimethylammonium phosphate. The combined organic layer was washed with brine, dried over anhydrous sodium 2SO4, and concentrated under reduced pressure to obtain some residue. The residue was purified by preparative HPLC to obtain 45 g (380 mg) of the compound as a yellow oil. LCMS(M+H) + ):701.

[0251] Step 8: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]6-fluoro-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45h) A mixture of water (3 mL) and THF (2 mL) containing O1-benzyl O2-methyl(2S,4S)-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 45 g, 380.0 mg, 0.54 mmol) and lithium hydroxide hydrate (114 mg, 2.71 mmol) was stirred at room temperature for 1 hour. The reaction mixture was quenched with water and then extracted three times with SiO2. The combined organic layer was washed with brine, dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain compound 45h (260.0 mg) as a yellow oil. LCMS(M+H + ):687.

[0252] Step 9: Preparation of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1-(methylaminomethyl)cyclopropyl]methyl]benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45i) (2S,4S)-1-benzyloxycarbonyl-4-[[6-[3-[[1-[[tert-butoxycarbonyl(methyl)amino]methyl]cyclopropyl]methyl]-6-fluoro-2-methyl-benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45h, 220.0 mg, 0.32 mmol) was dissolved in DCM (3 mL), to which 4 M HCl (1.0 mL) in dioxane was added, and the resulting mixture was stirred at room temperature for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain some crude product, which was then purified by silica gel column chromatography to obtain compound 45i (120.0 mg) as a white solid. LCMS(M+H + ):587.

[0253] Step 10: (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .18,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-10-carboxylate (compound 45j) A solution of (2S,4S)-1-benzyloxycarbonyl-4-[[6-[6-fluoro-2-methyl-3-[[1-(methylaminomethyl)cyclopropyl]methyl]benzimidazole-4-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 45i, 60.0 mg, 0.1 mmol) in DMF (50 mL) was added dropwise over 1 hour to a mixture of HATU (58.3 mg, 0.15 mmol) and DIPEA (0.1 mL, 0.51 mmol) in DMF (50 mL). The resulting mixture was stirred at room temperature for 2 hours. The reaction mixture was concentrated under reduced pressure to obtain some crude product, which was purified by reverse-phase flash column chromatography to obtain compound 45j (26.0 mg) as a yellow oil. LCMS(M+H + ):569.

[0254] Step 11: (8S,11S)-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one (compound 45k) (8S,11S)-22-fluoro-13,18-dimethyl-12-oxo-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24A mixture of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-10-carboxylate (compound 45j, 5.0 mg, 0.01 mmol) and methanol (3 mL) containing Pd / C (1.0 mg) was stirred under hydrogen at room temperature for 1 hour. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain compound 45k (3.0 mg) as a white solid, which was used in the next step without further purification. LCMS(M+H + ):434.

[0255] Step 12: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1 2,6 .1 8,11 .0 20,24 Preparation of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one (Example 45) (8S,11S)-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazapentacyclo[15.6.1.1] in ACN (1 mL) 2,6 .1 8,11 .0 20,24 A mixture of hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one (compound 45k, 3.0mg, 0.01mmol), 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (intermediate C2, 1.8mg, 0.01mmol), and DIPEA (2.6mg, 0.02mmol) was stirred at 80°C for 1 hour. After cooling to room temperature, the reaction mixture was directly purified by preparative HPLC to obtain Example 45 (1.1mg) as a white solid. LCMS(M+H) + ):665.

[0256] Example 46 (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0257] Step 1: tert-butyl(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaene-10-carboxylate (compound 46a-1) Compounds 46a-1 and 46a-2 were obtained by preparative HPLC of compound 46a (the synthesis of compound 46a was carried out by referring to compound 21c and using intermediate B8 instead of intermediate B10). LCMS(M+H) + ):551. The structure of compound 46a-1 was confirmed by X-ray single-crystal diffraction. (Figure 1)

[0258] Step 2: (8S,11S,18S)-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .18,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 46b-1) To a solution of compound 46a-1 (0.2 g, 0.36 mmol) in DCM (2 mL), TFA (2.0 mL) was added at 0°C, and the mixture was stirred at 20°C for 2 hours. The mixture was concentrated under reduced pressure to obtain a brown oily substance, which was purified by preparative HPLC to obtain compound 46b-1 (30.0 mg). LCMS(M+H) + ):451.

[0259] Steps 3-4: (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 46) Example 46 was prepared in the same manner as the preparation of Example 43, by using 3-oxa-6-azabicyclo[3.1.1]heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane, compound 46b-1 instead of compound 21d, and intermediate C5 instead of intermediate C3. LCMS(M+H + ):793. 1H NMR(400MHz,chloroform-d)δ=8.01(s,1H),7.69(t,J=7.8Hz,1H),7.63-7.57(m,1H),7.33-7.24(m,2H),6.95(d,J=7.6Hz,1H),6.72-6.64(m,2H),6.45(br d,J=8.4Hz,1H),5.43-5.27(m,1H),5.17-4.99(m,1H),4.72-4.57(m,1H),4.51-4.38(m,2H),4.37-4.20(m,4H),4.15(br s,2H),4.08-3.99(m,1H),3.87-3.70(m,3H),3.60(br d,J=9.6Hz,1H),3.41-3.31(m,1H),3.30-3.19(m,1H),3.17-3.08(m,1H),2 .99-2.92(m,2H),2.81-2.77(m,3H),2.46-2.22(m,3H),1.88-1.80(m,1H).

[0260] Example 47 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 47 was prepared in the same manner as in Example 43, but using 3-oxa-6-azabicyclo[3.1.1]heptane instead of 3-methyl-3,6-diazabicyclo[3.1.1]heptane (di-2,2,2-trifluoroacetate). LCMS(M+H + ):778. 1H NMR(400MHz,chloroform-d)δ=8.10(s,1H),7.82-7.76(m,1H),7.75-7.69(m,1H),7.59-7.48(m,1H),7.39-7.31(m,1H),7.25-7.14(m,1H),7.02(br t,J=8.4Hz,2H),6.54(d,J=8.4Hz,1H),5.43(d,J=8.4Hz,1H),5.28-5.06 (m,1H),4.77-4.64(m,1H),4.60-4.46(m,1H),4.46-4.34(m,2H),4.29(br s,2H),4.27-4.20(m,2H),4.19(s,1H),4.09(s,1H),4.05-3.95(m,1H),3.94-3.86(m,1H),3.85-3.77(m,1H),3.75(s,1H),3.70-3.62(m, 1H),3.50-3.38(m,1H),3.36-3.24(m,1H),3.20-3.09(m,1H),3.06-2 .95(m,1H),2.93-2.76(m,3H),2.75-2.15(m,2H),2.12-2.04(m,2H).

[0261] Examples 48 and 49 (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one and (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-on [ka] [ka] The title compound was prepared according to the following scheme. [ka]

[0262] Step 1: Preparation of tert-butyl N-[3-(2-bromo-6-nitro-anilino)propyl]-N-methyl-carbamate (compound 48b) A mixture of 3-bromo-2-fluoronitrobenzene (5.0 g, 22.73 mmol), compound 48a (5.5 g, 29.21 mmol), and triethylamine (3.0 g, 29.65 mmol) in THF (100 mL) was stirred at 20°C for 12 hours. The mixture was diluted with RINKAN (500 mL), washed with water (100 mL) and brine (100 mL), the organic layer was dried, and concentrated to obtain compound 48b (8.5 g) as a yellow oil. LCMS(M+2+H) + ):420.

[0263] Step 2: Preparation of tert-butyl N-[3-(2-amino-6-bromoanilino)-4-hydroxy-butyl]-N-methyl-carbamate (compound 48c) To a solution of compound 48b (4.0 g, 9.56 mmol) in methanol (40 mL), Raney Ni (2.25 g, 38.25 mmol) and hydrazine hydrate (3.2 g, 63.92 mmol) were slowly added. After stirring at 25°C for 1 hour, the mixture was filtered through Celite. The filtrate was concentrated at 20°C, and the crude product was dissolved in 60 mL of DCM. The DCM solution was washed with water (50 mL) and brine (50 mL), the organic layer was dried, and concentrated to obtain compound 48c (3.0 g) as a yellow oil. LCMS(M+2+H + ):390.

[0264] Step 3: Preparation of tert-butyl N-[3-[7-bromo-2-[[tert-butyl(dimethyl)silyl]oxymethyl]benzimidazole-1-yl]-4-hydroxy-butyl]-N-methyl-carbamate (compound 48d) To a solution of compound 48c (2.9 g, 7.47 mmol) in water (3 mL) and DMF (30 mL), oxone (1.26 g, 7.47 mmol) and (tert-butyldimethylsilyloxy)acetaldehyde (1.5 g, 8.59 mmol) were alternately added at 0°C, and the mixture was stirred at 20°C for 3 hours. The reaction mixture was quenched with saturated ammonium chloride solution (200 mL) and extracted with ethyl acetate. The organic layer was washed with brine (100 mL), dried, and concentrated to obtain compound 48d (3 g) as a brown oily substance. LCMS(M+2+H) + ):544.

[0265] Step 4: Preparation of tert-butyl N-[3-[7-bromo-2-(hydroxymethyl)benzimidazole-1-yl]-4-hydroxy-butyl]-N-methyl-carbamate (compound 48e) To a solution of compound 48d (3.0 g, 5.53 mmol) in methanol (30 mL), potassium fluoride (1.61 g, 27.65 mmol) was added, and the mixture was stirred at 65°C for 5 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by preparative HPLC to obtain compound 48e (1.7 g) as a brown oily substance. LCMS(M+2+H) + ):430.

[0266] Step 5: Preparation of tert-butyl N-[2-(6-bromo-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-4-yl)ethyl]-N-methyl-carbamate (compound 48f) To a solution of compound 48e (400 mg, 0.79 mmol) and tributylphosphan (482 mg, 2.38 mmol) in toluene (40 mL), (3E)-3-(dimethylcarbamoylimino)-1,1-dimethylurea (410 mg, 2.38 mmol) was added at 0°C, and the mixture was then stirred at 100°C for 1 hour. The reaction mixture was concentrated under reduced pressure, and the residue was purified by column chromatography to obtain compound 48f (300 mg) as a yellow oily substance. LCMS(M+H) + ):410.

[0267] Step 6: Preparation of tert-butyl N-methyl-N-[2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-4-yl]ethyl]carbamate (48g of compound) To a solution of compound 48f (400 mg, 0.97 mmol), bis(pinacolato)diborone (618.9 mg, 2.44 mmol), butyldi-1-adamantylphosphine (104.86 mg, 0.29 mmol), and bis(triphenylphosphine)palladium(II) chloride (103 mg, 0.15 mmol) in DMSO (2 mL), potassium acetate (0.12 mL, 1.95 mmol) was added, and the mixture was stirred at 110°C for 2 hours under N2. The reaction mixture was diluted with water (100 mL), extracted with ethyl acetate, the organic layer was dried, concentrated, and the residue was purified by column chromatography to obtain 48 g (300 mg) of compound as a yellow oil. LCMS(M+H) + ):458.

[0268] Step 7: Preparation of N-methyl-2-[6-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-4-yl]ethanamine (compound 48h) A solution of 48 g (300 mg, 0.07 mmol) of the compound in DCM (10 mL) was mixed with HCl / dioxane (4 mL) at 0°C and then stirred at 20°C for 2 hours. The reaction mixture was concentrated to obtain 48 h (300 mg) of the compound as a brown solid. LCMS(M+H) + ):358.

[0269] Step 8: Preparation of O1-tert-butylO2-methyl(2S,4S)-4-[[6-[4-[2-(methylamino)ethyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-6-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (compound 48i) A mixture of compound 48h (300 mg, 0.84 mmol), O1-tert-butyl O2-methyl(2S,4S)-4-[(6-bromo-2-pyridyl)amino]pyrrolidine-1,2-dicarboxylate (336 mg, 0.84 mmol), 1,1'-bis(diphenylphosphino)ferrocene-palladium(II) dichloride dichloromethane complex (137 mg, 0.17 mmol), and potassium carbonate (232 mg, 1.68 mmol) in 1,4-dioxane (10 mL) and water (2 mL) was stirred at 100°C for 5 hours. The reaction mixture was filtered, and the filtrate was concentrated under reduced pressure to obtain crude compound 48i (600 mg) as a brown oily substance. LCMS(M+H + ):551.

[0270] Step 9: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[4-[2-(methylamino)ethyl]-3,4-dihydro-1H-[1,4]oxazino[4,3-a]benzimidazole-6-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 48j) A solution of compound 48i (600 mg, 1.09 mmol) in THF (3 mL) and methanol (3 mL) was added at 0°C to a solution of LiOH·H2O (134.02 mg, 3.27 mmol) in water (3 mL), and the mixture was stirred at 20°C for 2 hours. The reaction mixture was concentrated under reduced pressure, and the residue was purified by reverse-phase flash column chromatography to obtain compound 48j (200 mg) as a brown solid. LCMS(M+H + ):537.

[0271] Step 10: tert-butyl(13R,18S,21S)-16-methyl-17-oxo-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaene-19-carboxylate (compound 48k-1) and tert-butyl(13S,18S,21S)-16-methyl-17-oxo-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaene-19-carboxylate (compound 48k-2) A solution of compound 48j (200 mg, 0.37 mmol) in DMF (300 mL) was added at 0°C to a solution of HATU (212.6 mg, 0.56 mmol) and DIPEA (0.13 mL, 0.75 mmol) in DMF (100 mL), and then stirred at 20°C for 0.5 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC, yielding compound 48k-1 (50 mg) as a white solid and compound 48k-2 (30 mg) as a yellow solid. LCMS(M+H) was then used to purify the mixture. + ):519.

[0272] Step 11: (13R,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (compound 48l-1) and (13S,18S,21S)-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (compound 48l-2) To a solution of compound 48k-1 (50 mg, 0.1 mmol) in DCM (2 mL), TFA (2.0 mL) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 48l-1 (50 mg) as a brown oily substance. LCMS(M+H) + ):419.

[0273] To a solution of compound 48k-2 (30 mg, 0.06 mmol) in DCM (2 mL), TFA (2.0 mL) was added at 0°C, and the mixture was then stirred at 20°C for 1 hour. The reaction mixture was concentrated under reduced pressure to obtain compound 48l-2 (30 mg) as a brown oily substance. LCMS(M+H) + ):419.

[0274] Step 12: (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (Example 48) and (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaen-17-one (Example 49) To a solution of compound 48l-1 (50 mg, 0.12 mmol) and 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (32 mg, 0.12 mmol) in ACN (1 mL), N,N-diisopropylethylamine (0.04 mL, 0.24 mmol) was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 48 (21 mg) as a white solid. LCMS(M+H) + ):649. 1 H NMR(400MHz, methanol-d4)δ=8.44(s,1H),8.11(s,1H),7.96-7.85(m,1H),7.72(d,J=8.4Hz,1H),7.61-7.51(m,1H),7.45(br t,J=8.0Hz,1H),7.25(br d,J=6.8Hz,1H),7.21-7.15(m,1H),7.10(br t,J=7.6Hz,1H),6.99(br d,J=8.4Hz,1H),6.86(br d,J=7.2Hz,1H),5.39(d,J=8.8Hz,1H),5.29-5.14(m,1H),5.09-4.98(m,1H),4.45( dd,J=6.0,11.6Hz,1H),4.38-4.11(m,3H),4.02-3.86(m,4H),3.05(s,3H),2.88(br t,J=4.4Hz,1H),2.56-2.34(m,3H).

[0275] To a solution of compound 48l-2 (30 mg, 0.07 mmol) and 4-chloro-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine (19 mg, 0.07 mmol) in ACN (2 mL), N,N-diisopropylethylamine (0.02 mL, 0.14 mmol) was added, and the mixture was stirred at 80°C for 2 hours. The reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 49 (15 mg) as a white solid. LCMS(M+H) + ):649. 1 H NMR (400MHz, methanol-d4)δ=8.46(s,1H),8.15(s,1H),7.80-7.71(m,2H),7.66-7.60(m,1H),7.59-7.51(m,2H),7.25-7.17(m,1H),7.15-7.08(m ,1H),7.08-7.02(m,1H),6.66(d,J=8.4Hz,1H),5.36(d,J=8.8Hz,1H),5 .21(s,1H),5.14(s,1H),4.65-4.54(m,1H),4.53-4.28(m,2H),4.24(br d,J=11.6Hz,2H),3.94(br d,J=13.2Hz,3H),2.86(s,4H),2.82-2.33(m,3H).

[0276] Example 50 (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-9,12,16,19,22,27,29heptazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Nonacosa-1(26),2,4,6(29),7,23(27),24-Heptaene-11,17-Zeon [ka] The title compound was prepared according to the following scheme. [ka]

[0277] Step 1: Preparation of benzyl N-(3-hydroxypropyl)-N-methylcarbamate (compound 50b) A mixture of THF (100 mL) and water (100 mL) containing N-(benzyloxycarbonyloxy)succinimide (33.55 g, 134.62 mmol), sodium carbonate (23.78 g, 224.37 mmol), and compound 50a (10.0 g, 112.18 mmol) was stirred at 20°C for 1 hour. The mixture was then diluted with water (100 mL), extracted with toluene (600 mL), the organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 50b (20 g) as a colorless oil. LCMS(M+H + ):224.

[0278] Step 2: Preparation of benzyl N-methyl-N-(3-oxopropyl)carbamate (compound 50c) To a solution of compound 50b (2.0 g, 8.96 mmol) in DCM (20 mL), DMP (4.56 g, 10.75 mmol) was added at 0°C, and the mixture was then stirred at 20°C for 2 hours. The reaction mixture was then poured into 40 mL of siRNA / PE (1:10), the solid was filtered off, and the filtration was concentrated to obtain crude compound 50c (2 g) as a pale yellow residue, which was used directly without further purification. LCMS(M+H + ):222.

[0279] Step 3: Preparation of N-[2-(10-bromo-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazole-1-yl)ethyl]-N-methylcarbamate benzyl (compound 50d) To a solution of compound 50c (1.5 g, 6.78 mmol) in DCM (20 mL), 2-methyl-2-propanesulfinamide (822 mg, 6.78 mmol), MgSO4 (814 mg, 6.78 mmol), and pyridinium tosylate (1.7 g, 6.78 mmol) were added. After stirring under N2 at 25°C for 16 hours, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 50d (2 g) as a colorless oil. LCMS(M+H) + ):325.

[0280] Step 4: Preparation of 2-[(4-bromoindazole-2-yl)methoxy]ethyl-trimethyl-silane (compound 50f) To a solution of compound 50e (3 g, 15.23 mmol) in THF (150 mL), (2-(chloromethoxy)ethyl)trimethylsilane (3.05 g, 18.27 mmol) and dicyclohexylmethylamine (3.6 g, 18.27 mmol) were added at 20°C. After stirring at 25°C for 18 hours, the reaction mixture was concentrated, and the residue was purified by silica gel column chromatography to obtain compound 50f (2.4 g) as a white solid. LCMS(M+2+H) + ):329.

[0281] Step 5: Preparation of N-[3-[4-bromo-2-(2-trimethylsilylethoxymethyl)indazole-3-yl]-3-(tert-butylsulfinylamino)propyl]-N-methylcarbamate benzyl (50g of compound) To a solution of compound 50f (17.15 g, 52.4 mmol) in THF (250 mL), LDA in THF (31 mL, 62 mmol) was added under an N2 atmosphere at -78°C for 1 hour. After stirring under an N2 atmosphere at -78°C for 30 minutes, a solution of compound 50d (10.0 g, 30.82 mmol) in THF (50 mL) was added dropwise to the reaction mixture over 1 hour. The reaction mixture was stirred at -78°C for 1 hour, then the reaction was quenched with saturated NH4Cl aqueous solution, and the resulting mixture was extracted with RINKAN. The organic layer was dried over Na2SO4, concentrated, and the residue was purified by silica gel column chromatography to obtain 50 g (10.0 g) of compound as a pale yellow oil. LCMS(M+H + ):651.

[0282] Step 6: Preparation of N-[3-amino-3-(4-bromo-2H-indazole-3-yl)propyl]-N-methylcarbamate benzyl (compound 50h) To a solution of 50 g (2.0 g, 3.07 mmol) of the compound in methanol (10 mL), aqueous HCl (10.0 mL, 60.0 mmol) was added. After stirring at 70°C for 2 hours, the mixture was concentrated to obtain 50 h (1.3 g) of the compound as a pale yellow semi-solid. LCMS(M+2+H) + ):419.

[0283] Step 7: Preparation of N-[3-(4-bromo-2H-indazole-3-yl)-3-[(2-chloroacetyl)amino]propyl]-N-methylcarbamate benzyl (compound 50i) To a solution of compound 50h (1.3 g, 3.12 mmol) and NaHCO3 (524 mg, 6.23 mmol) in water (30 mL), chloroacetyl chloride (352 mg, 3.12 mmol) in DCM (20 mL) was added at 0°C. After stirring at 25°C for 16 hours, the reaction mixture was extracted with DCM. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 50i (500 mg) as a colorless oil. LCMS(M+2+H + ):495.

[0284] Step 8: Preparation of N-[3-amino-3-(4-bromo-2H-indazole-3-yl)propyl]-N-methylcarbamate benzyl (compound 50j) Compound 50i (300 mg, 0.61 mmol) from ACN (100 mL) was slowly added at 80°C to a suspension of cesium carbonate (198 mg, 0.61 mmol) in ACN (50 mL). After stirring at 80°C for 3 hours, the reaction mixture was filtered, the filtrate was concentrated, and the residue was purified by preparative HPLC to obtain compound 50j (150 mg) as a white solid. LCMS(M+2+H) + ):459.

[0285] Step 9: Preparation of N-methyl-N-[2-[3-oxo-10-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)-2,4-dihydro-1H-pyrazino[1,2-b]indazole-1-yl]ethyl]benzyl carbamate (compound 50k) A mixture of compound 50j (200 mg, 0.44 mmol), potassium acetate (86 mg, 0.87 mmol), Pd(dppf)Cl2 (18 mg, 0.02 mmol), and bis(pinacorato)diborone (167 mg, 0.66 mmol) in 1,4-dioxane (5 mL) was stirred under N2 at 80°C for 16 hours. The mixture was then filtered, and the filtrate was concentrated to obtain crude compound 50k (220 mg) as a black oily substance, which was used directly without further purification. LCMS(M+H + ):505.

[0286] Step 10: Preparation of O1-tert-butylO2-methyl(2S,4S)-4-[[6-[1-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazole-10-yl]-2-pyridyl]amino]pyrrolidine-1,2-dicarboxylate (50L of compound) A mixture of intermediate B8 (175 mg, 0.44 mmol), compound 50k (220.0 mg, 0.44 mmol)Pd(dppf)Cl2 (71 mg, 0.09 mmol), and potassium carbonate (181 mg, 1.3 mmol) in 1,4-dioxane (5 mL) and water (0.5 mL) was stirred at 100°C for 2 hours under N2. The mixture was then concentrated, and the residue was purified by preparative TLC to obtain compound 50l (250 mg) as a light brown oily substance. LCMS(M+H + ):698.

[0287] Step 11: Preparation of (2S,4S)-4-[[6-[1-[2-[benzyloxycarbonyl(methyl)amino]ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazole-10-yl]-2-pyridyl]amino]-1-tert-butoxycarbonylpyrrolidine-2-carboxylic acid (compound 50m) A mixture of 50 ml (250 mg, 0.36 mmol) of the compound and lithium hydroxide monohydrate (75 mg, 1.79 mmol) in methanol (4 mL) and water (2 mL) was stirred at 25°C for 8 hours. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to obtain 50 ml (70 mg) of the compound as a yellow solid. LCMS(M+H) + ):684.

[0288] Step 12: Preparation of (2S,4S)-1-tert-butoxycarbonyl-4-[[6-[1-[2-(methylamino)ethyl]-3-oxo-2,4-dihydro-1H-pyrazino[1,2-b]indazole-10-yl]-2-pyridyl]amino]pyrrolidine-2-carboxylic acid (compound 50n) To a solution of 50m (60mg, 0.09 mmol) of compound in 2-propanol (7mL) and THF (7mL), Pd / C (60mg) was added under N2 conditions. The mixture was then stirred under hydrogen at 50°C for 4 hours. The reaction mixture was filtered, and the filtrate was concentrated to obtain crude compound 50n (35mg) as a pale yellow solid. LCMS(M+H + ): 550.

[0289] Step 13: tert-butyl(18S,21S)-16-methyl-11,17-dioxo-9,12,16,19,22,27,29heptazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene-19-carboxylate (compound 500) To a solution of DIPEA (0.03 mL, 0.18 mmol) and HATU (35 mg, 0.09 mmol) in DMF (5 mL), a solution of compound 50n (40.0 mg, 0.07 mmol) in DMF (5 mL) was added dropwise at 0°C for 1 hour. The mixture was then concentrated, and the residue was purified by preparative TLC to obtain compound 50o (30 mg) as a pale yellow oily substance. LCMS(M+H + ):532.

[0290] Step 14: (18S,21S)-16-methyl-9,12,16,19,22,27,29 heptazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13 Preparation of nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione; 2,2,2-trifluoroacetic acid (compound 50p) A mixture of compound 50o (30 mg, 0.06 mmol) in DCM (5 mL) and TFA (1 mL) was stirred at 20°C for 2 hours. The reaction product was then concentrated to obtain compound 50p (20 mg) as a pale yellow oily substance. LCMS(M+H + ):432.

[0291] Step 15: (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-9,12,16,19,22,27,29heptazahexacyclo[21.3.1.1 6,9 .1 18,21 .0 2,7 .0 8,13Preparation of nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene-11,17-dione (Example 50) A mixture of compound 50p (20 mg, 0.05 mmol), DIPEA (0.02 mL, 0.12 mmol), and intermediate C2 (13 mg, 0.05 mmol) in ACN (2 mL) was stirred at 80°C for 2 hours. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to obtain Example 50 (1.2 mg) as a light brown solid. LCMS(M+H) + ):662. 1 H NMR (400MHz, methanol-d4) δ=8.57(s,1H),8.28(s,1H),7.84-7.79(m,1H),7.74-7 .67(m,2H),7.48-7.40(m,2H),7.37-7.30(m,1H),7.26-7.18(m,2H),6.71-6.64 (m,1H),6.26-6.16(m,1H),5.56(d,J=8.4Hz,1H),5.30-5.22(m,1H),5.13-5.06 (m,1H),4.61-4.54(m,1H),4.42-4.34(m,1H),3.1(s,1H),3.03(s,3H),1.76(br d,J=8.0Hz,2H),1.64-1.57(m,2H),1.51-1.43(m,2H).

[0292] Example 51 (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,16,22,24,31heptazahexacyclo[20.6.1.1 2,6 .1 8,11 .0 13,18 .0 25,29 ]Hentriakonta-1(29),2,4,6(31),23,25,27Heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0293] Step 1: Preparation of O4-benzyl O1-tert-butyl O2-methylpiperazine-1,2,4-tricarboxylate (compound 51b) A mixture of compound 51a (10 g, 40.93 mmol) and triethylamine (8 mL, 61.4 mmol) in DCM (200 mL) was mixed with benzyl carbonochloride (7 g, 45.03 mmol) under N2 at 0°C. The mixture was stirred at 25°C for 3 hours, and then the reaction was quenched with water (100 mL). After separation, the organic layer was washed with 5% citric acid, saturated NaHCO3, and brine. The organic layer was dried and concentrated to obtain the desired compound 51b (15 g). LCMS(M+H) + ):379.

[0294] Step 2: Preparation of O4-benzyl O1-tert-butyl 2-(hydroxymethyl)piperazine-1,4-dicarboxylate (compound 51c) To a solution of compound 51b (22 g, 58.14 mmol) and CaCl2 (9 g, 81.39 mmol) in ethanol (200 mL) and THF (200 mL), sodium borohydride (4 g, 116.27 mmol) was added at 0°C and the mixture was stirred at 20°C for 16 hours. The reaction mixture was quenched with saturated ammonium chloride solution (1000 mL) and extracted with ethyl acetate. The organic layer was washed with water and brine (200 mL), dried over anhydrous Na2SO4, and concentrated under reduced pressure to obtain crude product compound 51c (19 g). LCMS(M+H) + ):351.

[0295] Step 3: Preparation of O4-benzyl O1-tert-butyl2-formylpiperazine-1,4-dicarboxylate (compound 51d) To a solution of compound 51c (12 g, 34.25 mmol) in DCM (120 mL), dess-martin peridinane (29 g, 68.49 mmol) was added at 0°C for 30 minutes, and then the mixture was heated to 20°C for 4 hours. The reaction mixture was poured into a solution (120 mL saturated sodium dicarbonate solution, 120 mL saturated sodium bisulfite solution), extracted with DCM (20 ml x 3), the organic layer was dried over Na2SO4, filtered, and concentrated. The residue was purified by silica gel column chromatography to obtain compound 51d (3.2 g). LCMS(M+H) + ):349.

[0296] Step 4: Preparation of O4-benzyl O1-tert-butyl 2-(3-ethoxy-3-oxopropa-1-enyl)piperazine-1,4-dicarboxylate (compound 51e) To a solution of compound 51d (3g, 9.19 mmol) in toluene (30 mL), (carbetoxymethylene)triphenylphosphorane (3g, 10.1 mmol) was added and the mixture was stirred at 105°C for 16 hours. The reaction mixture was concentrated and purified by preparative HPLC to obtain compound 51e (3g). LCMS(M+H) + ):319.

[0297] Step 5: Preparation of O4-benzyl O1-tert-butyl 2-(3-ethoxy-3-oxopropyl)piperazine-1,4-dicarboxylate (compound 51f) A mixture of compound 51e (2 g, 5.02 mmol) and PtO2 (200 mg, 5.02 mmol) in anhydrous THF (20 mL) was stirred at 20°C for 2 hours under a hydrogen balloon. The mixture was filtered and concentrated to obtain compound 51f (2 g), which was used directly in the next step. LCMS(M+H + ):321.0

[0298] Step 6: Preparation of O4-benzyl O1-tert-butyl 2-(3-hydroxypropyl)piperazine-1,4-dicarboxylate (51 g of compound). A mixture of compound 51f (3 g, 7.13 mmol) and CaCl2 (1 g, 10.81 mmol) in anhydrous THF (15 mL) and ethanol (15 mL) was mixed with sodium borohydride (600 mg, 15.86 mmol), and then stirred at 20°C for 12 hours. The mixture was diluted with DCM (100 mL) and then poured into ice-NH4Cl aqueous solution (100 mL). The organic layer was separated, dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain compound 51 g (2 g). LCMS(M+H + ):279.

[0299] Step 7: Preparation of O4-benzyl O1-tert-butyl 2-[3-(1,3-dioxoisoindorin-2-yl)propyl]piperazine-1,4-dicarboxylate (compound 51h) To a solution of 51 g (2 g, 6.34 mmol) of compound, phthalimide (1 g, 9.52 mmol), and triphenylphosphine (2 g, 9.15 mmol) in anhydrous THF (20 mL), DEAD (2 g, 9.19 mmol) in a glove box was added under Ar, and the reaction solution was stirred at 20°C for 12 hours. The mixture was diluted with SiO (100 mL) and then washed with water (50 mL) and brine (50 mL). The organic layer was dried over anhydrous Na2SO4, filtered, and concentrated to obtain the crude product, which was purified by preparative HPLC to obtain compound 51h (3.0 g). LCMS(M-Boc+H) + ):408.

[0300] Step 8: Preparation of O4-benzyl O1-tert-butyl 2-(3-aminopropyl)piperazine-1,4-dicarboxylate (compound 51i) A mixture of compound 51h (3 g, 5.71 mmol) and hydrated monomethylamine (5.0 mL, 5.71 mmol) was dissolved in ethanol (10 mL) and stirred at 70°C for 12 hours. The mixture was diluted with DCM (100 mL), washed with water and brine, and the organic layer was dried and concentrated to obtain compound 51i (2 g). LCMS(M+H) + ):378.

[0301] Steps 9-12: Preparation of O4-benzyl O1-tert-butyl 2-[3-[7-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl)benzimidazole-1-yl]propyl]piperazine-1,4-dicarboxylate (compound 51m) Compound 51m was prepared in the same manner as the preparation of intermediate A1, by using compound 51i instead of compound tert-butyl 6-(aminomethyl)-1,4-oxazepan-4-carboxylate. LCMS(M+H + ):605.

[0302] Steps 13-17: Benzyl(8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[4,3-c]pyridine-4-yl]-12-oxo-7,10,13,16,22,24,31heptazahexacyclo[20.6.1.1 2,6 .1 8,11 .0 13,18 .0 25,29 Preparation of Hentriaconta-1(29),2,4,6(31),23,25,27 heptaene-16-carboxylate (compound 51s) Compound 51s was prepared in the same manner as in Example 1, by using compound 51m instead of intermediate A1. LCMS(M+H + ):796.

[0303] Step 18: (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,16,22,24,31heptazahexacyclo[20.6.1.1 2,6 .1 8,11 .0 13,18 .0 25,29 Preparation of Hentriaconta-1(29),2,4,6(31),23,25,27heptaen-12-one (Example 51) A mixture of compound 51s (20 mg, 0.03 mmol) and trifluoroacetic acid (2 mL, 25.96 mmol) was stirred at 70°C for 1 hour. The mixture was concentrated to obtain the crude product, which was purified by preparative HPLC to obtain Example 51 (3 mg). LCMS(M+H)+ ):662. 1 H NMR(400MHz,DMSO-d6)δ=9.25(br s,1H),8.56(br s,1H),8.27-8.50(m,1H),7.93-8.11(m,1H),7.70-7.72(m,1H),7.64-7.69(m,1H),7.49-7.51(m ,1H),7.47-7.48(m,1H),7.25-7.29(m,1H),7.15-7.23(m,1H),7.06-7.11(m,1H),6.75-6.81(m,1 H),6.54-6.57(m,2H),5.33-5.36(m,1H),4.33-4.39(m,2H),4.30-4.31(m,1H),4.14-4.19(m,2H ),4.05-4.09(m,3H),3.69-3.70(m,2H),2.65-2.70(m,2H),1.91-1.95(m,2H),0.98-1.17(m,4H).

[0304] Example 52 (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl]pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 52 was prepared according to the following scheme. [ka]

[0305] Step 1: tert-butyl3-[[4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]-1-[4-fluoro-2-(triduteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidine-6-yl]methyl]azetidine-1-carboxylate (compound 52a) A mixture of DME (2 mL) containing compound 46c (270 mg, 0.37 mmol), tert-butyl 3-(iodomethyl)azetidine-1-carboxylate (143 mg, 0.48 mmol), Ir[dF(CF3)ppy]2(dtbpy)(PF6) (4 mg, 0.04 mmol), NiCl2·dtbbpy (2 mg, 0.02 mmol), TTMSS (92 mg, 0.37 mmol), and Na2CO3 (78 mg, 0.74 mmol) was stirred and irradiated with a 34 W blue LED lamp at 25°C for 14 hours. The reaction mixture was then filtered, the filtrate was concentrated, and the residue was purified by reverse-phase flash column chromatography to obtain compound 52a (140 mg) as a yellow solid. LCMS(M+H + ):865.

[0306] Step 2: (8S,11S,18S)-10-[6-(azetidine-3-ylmethyl)-1-[4-fluoro-2-(triduteriomethoxy)phenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 52b) To a solution of compound 52a (34 mg, 0.04 mmol) in DCM (0.5 mL), TFA (3 mL) was added at 0°C. After stirring at 25°C for 1 hour, the reaction mixture was concentrated, and the residue was purified by reverse-phase flash column chromatography to obtain compound 52b (20 mg) as a white solid. LCMS(M+H + ):765.

[0307] Step 3: (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl]pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 52) Compound 52b (20 mg, 0.02 mmol) and 2,2,2-trifluoroethyltrifluoromethanesulfonate (6 mg, 0.03 mmol) were dissolved in THF (1 mL), to which TEA (4 mg, 0.03 mmol) was added. After stirring at 60°C for 16 hours, the reaction mixture was concentrated, and the residue was purified by preparative HPLC to obtain Example 52 (6.8 mg) as a white solid. LCMS(M+H) + ):847. 1H NMR (400MHz, acetonitrile-d3) δ=8.25(s,1H),7.77-7.63(m,1H),7.43-7.34(m,1H),7.30 (dd,J=2.6,9.0Hz,1H),7.08(dd,J=2.6,10.9Hz,1H),7.02-6.92(m,2H),6.86(dt,J=2 .6,8.4Hz,1H),6.60(d,J=8.3Hz,1H),6.11-5.94(m,1H),5.46-5.20(m,1H),5.18-4.9 6(m,1H),4.70-4.59(m,1H),4.50(dd,J=6.5,11.3Hz,1H),4.29-4.14(m,2H),4.10(br d,J=15.4Hz,1H),3.93(br dd,J=4.3,14.1Hz,1H),3.84(dd,J=6.8,9.9Hz,1H),3.60-3.46(m,2H),3.40-3.32(m,1H),3.29-3.24(m,1H),3.20- 3.07(m,2H),3.05-3.02(m,2H),2.86-2.76(m,2H),2.67-2.58(m,1H),2.53-2.48(m,3H),2.47-2.38(m,1H),2.21(br dd,J=1.9,3.5Hz,1H),2.13-2.10(m,1H),1.49(br d,J=13.9Hz,1H),1.36-1.23(m,1H).

[0308] Example 53 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 53 was prepared in the same manner as in the preparation of Example 58, but by using intermediate C80 instead of compound 58f. LCMS(M+H) + :823. 1 ¹H NMR (400MHz, methanol-d4) δ=8.28 (d, J=1.1Hz, 1H), 7.77 (t, J=8.0Hz, 1H), 7.66-7.57 (m, 1H), 7.28 (dd, J=2.5, 8.5Hz, 1H), 7.26-7.19 (m, 1H), 7.18-7.13 (m, 1H), 7.11 (dd, J=2.6, 10.6Hz, 1H), 6.98-6.94 (m, 1H), 6.68 (br d,J=8.3Hz,1H),6.07-5.91(m,1H),5.47-5.36(m,1H),4.73-4.65(m,1H),4.59(s,5H),4.54-4.43(m,2H) ,4.40-4.33(m,1H),4.33-4.26(m,1H),4.26-4.16(m,3H),4.15-4.06(m,1H),4.03-3.94(m,1H),3.85(br dd,J=6.5,10.5Hz,1H),3.46-3.40(m,1H),3.37(br d,J=4.8Hz,1H),3.24(br d,J=11.6Hz,1H),3.12-2.99(m,1H),2.89(br d,J=10.0Hz,2H),2.77-2.67(m,2H),2.57(s,3H),2.49-2.43(m,1H),1.88(d,J=8.0Hz,1H),1.51(br d,J=12.4Hz,1H).

[0309] Example 54 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 54 was prepared in the same manner as in the preparation of Example 58, but by using intermediate C83 instead of compound 58f. LCMS(M+H + ):823. 1 H NMR (400MHz, methanol-d4)δ=8.20(s,1H),7.76(t,J=7.9Hz,1H),7.68-7.59(m,1H),7.28(dd,J=2.5,8.4H z,1H),7.25-7.18(m,1H),7.18-7.13(m,1H),7.10(dd,J=2.3,10.6Hz,1H),6.98-6.92(m,1H),6.65(br d,J=8.3Hz,1H),6.06-5.89(m,1H),5.52-5.30(m,1H),4.69-4.62(m,1H),4.56(br d,J=5.0Hz,1H),4.50-4.41(m,2H),4.29-4.19(m,1H),4.19-4.07(m,3H),4.07-3.96(m,1H),3.84(br dd,J=6.6,9.3Hz,1H),3.71(br d,J=11.1Hz,1H),3.45-3.33(m,3H),3.29-3.16(m,2H),3.12-3.01(m,1H),2.96-2.80(m, 3H),2.73-2.62(m,2H),2.58-2.53(m,3H),2.50-2.38(m,1H),1.95-1.88(m,1H),1.84(br d,J=7.3Hz,1H),1.50(br d,J=13.8Hz,1H),1.35(dd,J=1.8,6.5Hz,1H).

[0310] Example 55 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .113,18 .0 23,27 Triaconta-1(27),2,4,6(30),21,23,25heptaen-12-one [ka] Example 55 was prepared in the same manner as in the preparation of Example 58, but by using intermediate C89 instead of compound 58f. LCMS(M+H + ):833. 1 H NMR (400MHz, acetonitrile-d3) δ=8.19(d,J=2.9Hz,1H),7.79-7.71(m,1H),7.68-7.56(m,1H),7.34(br d,J=8.9Hz,1H),7.24-7.07(m,3H),6.96(d,J=7.5Hz,1H),6.62(dd,J=2.2,8.3Hz,1H),5.96(br dd,J=10.6,15.8Hz,1H),5.37(br d,J=9.3Hz,1H),4.69-4.36(m,6H),4.29-4.05(m,5H),3.97-3.71(m,3H),3.55(br dd,J=2.3,7.0Hz,1H),3.33(br d,J=11.6Hz,2H),3.24-3.15(m,4H),2.81-2.73(m,2H),2.60(br d,J=13.9Hz,1H),2.51(br d,J=1.8Hz,3H),2.47(br d,J=6.0Hz,2H),1.81(br d,J=7.0Hz,1H),1.49(br d,J=13.6Hz,1H).

[0311] Example 56 (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27Triaconta-1(27),2,4,6(30),21,23,25heptaen-12-one [ka] Example 56 was prepared in the same manner as in the preparation of Example 58, but by using intermediate C81 instead of compound 58f. LCMS(M+H + ):841. 1 H NMR (400MHz, methanol-d4)δ=8.26(s,1H),7.75(t,J=7.9Hz,1H),7.67-7.52(m,1H),7.33-7.19(m, 2H),7.18-7.07(m,2H),6.96(d,J=7.5Hz,1H),6.64(d,J=8.4Hz,1H),6.07-5.91(m,1H),5.40(br d,J=8.9Hz,1H),4.65-4.57(m,2H),4.45(br dd,J=6.4,11.3Hz,1H),4.27-4.06(m,5H),3.95(br dd,J=3.3,14.4Hz,1H),3.84(br dd,J=6.6,10.1Hz,1H),3.61(d,J=7.0Hz,1H),3.45-3.34(m,3H),3.29-3.18(m,2H),3.07-3.01(m,1H),2.97(br d,J=18.9Hz,1H),2.93-2.84(m,2H),2.83-2.76(m,1H),2.68(br d,J=13.5Hz,1H),2.54(s,3H),2.52-2.38(m,2H),1.75(d,J=8.0Hz,1H),1.48(br d,J=14.5Hz,1H).

[0312] Example 57 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .023,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 57 was prepared in the same manner as in the preparation of Example 58, but by using intermediate C88 instead of compound 58f. LCMS(M+H + ):833. 1 ¹H NMR (400MHz, methanol-d4) δ=8.23(s,1H),7.77(t,J=8Hz,1H),7.68-7.57(m,1H),7.28(dd,J=2.6,8.4Hz,1H),7.25-7.18(m,1H),7.18-7.13(m,1H),7.11(dd,J=2.6,10.6Hz,1H),6.99-6.91(m,1H),6.67(d,J=8.2Hz,1H),6.07- 5.89(m,1H),5.53-5.34(m,1H),4.74-4.70(m,2H),4.69-4.66(m,1H),4.54-4.48(m,2H),4.48-4.43(m,1H),4. 22-4.11(m,3H),4.07-3.96(m,2H),3.85(dd,J=6.8,10.0Hz,1H),3.58-3.52(m,1H),3.50-3.40(m,2H),3.38(br d,J=3Hz,1H),3.35(s,3H),3.27(br d,J=10.4Hz,1H),3.15-3.03(m,1H),2.93-2.83(m,1H),2.82-2.78(m,1H),2.71(br d,J=13.6Hz,1H),2.58-2.55(m,3H),2.47(ddd,J=4.6,9.0,13.6Hz,1H),1.97-1.80(m,2H),1.58-1.48(m,1H).

[0313] Example 58 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .113,18 .0 23,27 ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonilicate [ka] The title compound was prepared according to the following scheme. [ka]

[0314] Step 1: Preparation of methyl 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carboxylate (compound 58b) A mixture of compound C80-a (400 mg, 1.07 mmol), azetidine-3-carboxylate methyl hydrochloride (488.0 mg, 3.22 mmol), and DIPEA (1.39 g, 10.73 mmol) in acetonitrile (50 mL) was stirred at 90°C for 16 hours. The reaction solution was then concentrated, the residue was dissolved in EA, washed with water and brine, the organic layer was dried and concentrated to obtain compound 58b (500 mg), LCMS(M+H). + ):452.

[0315] Step 2: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carboxylic acid (compound 58c) A mixture of compound 58b (400 mg, 0.88 mmol) and lithium hydroxide (2.22 mL, 2 M) in methanol (8 mL) was stirred at room temperature for 4 hours, then the pH was adjusted to 6 and the mixture was diluted with water. The resulting mixture was extracted twice with EA, then the organic layer was dried and concentrated to obtain compound 58c (380 mg), LCMS(M+H). + ):438.

[0316] Step 3: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carboxamide (compound 58d) Compound 58c (380 mg, 0.61 mmol), ammonium chloride (325 mg, 6.08 mmol), DIPEA (786 mg, 6.08 mmol), and HATU (462 mg, 1.22 mmol) were mixed in tetrahydrofuran (10 mL) and stirred at 40°C for 2 hours. The reaction mixture was then concentrated, and the residue was purified by silica gel column chromatography to obtain compound 58d (300 mg). LCMS(M+H + ):437.

[0317] Step 4: Preparation of 1-[4-benzyloxy-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile (compound 58e) To a mixture of compound 58d (280 mg, 0.65 mmol) and pyridine (253.75 mg, 3.21 mmol) in DCM (28 mL), TFAA (404 mg, 1.92 mmol) was added dropwise at room temperature. After stirring at room temperature for 10 minutes, the reaction mixture was diluted with DCM, washed with water and brine, the organic layer was dried, and concentrated to obtain compound 58e (260 mg). LCMS(M+H) + ):419.

[0318] Step 5: Preparation of 1-[1-(2,4-difluorophenyl)-4-hydroxy-pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile (compound 58f) A mixture of compound 58e (240 mg, 0.49 mmol) in DCM (10 mL) and TFA (2 mL) was stirred at room temperature for 20 hours, and the reaction product was then concentrated to obtain compound 58f (120 mg). LCMS(M+H) + ):329.

[0319] Step 6: 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitrile (Example 58) A mixture of compound 58f (35 mg, 0.1 mmol), PyBOP (70 mg, 0.13 mmol), and DIPEA (57 mg, 0.44 mmol) in DMF (2 mL) was stirred at 50°C for 3 hours. Then, compound 46b-1 (40 mg, 0.09 mmol) was added, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was directly purified by preparative HPLC to obtain Example 58 (20 mg). LCMS(M+H) + ):761. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.26-8.12 (m,1H), 7.75-7.61 (m,1H), 7.56-7.49 (m,1H), 7.19-7.10 (m,2H), 7.07-6.98 (m,2H), 6.89-6.80 (m,1H), 6.64-6.50 (m,1H), 5.96-5.78 (m,1H), 5.39-5.23 (m,1H), 4.60-4.55 (m,1H), 4.50- 4.43(m,1H),4.43-4.35(m,1H),4.34-4.23(m,1H),4.22-3.85(m,8H),3.81-3.72(m,1H),3.67-3.46(m,2H),3. 40-3.31(m,1H),3.08-2.95(m,1H),2.81-2.58(m,1H),2.56-2.42(m,3H),2.41-2.30(m,1H),2.12-1.86(m,1H).

[0320] Example 59 (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0321] Step 1: tert-butyl6-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]-3,6-diazabicyclo[3.1.1]heptan-3-carboxylate (compound 59a) Compound 42a-2 (200 mg, 0.28 mmol), 3,6-diazabicyclo[3.1.1]heptane-3-carboxylic acid tert-butyl ester (222 mg, 1.12 mmol), CsF (127 mg, 0.84 mmol), and DIPEA (181 mg, 1.4 mmol) were mixed in dimethyl sulfoxide (5 mL) and stirred at 110°C for 16 hours. The reaction solution was then diluted with EA, washed with water and brine, and the organic layer was dried and concentrated to obtain compound 59a (245 mg) as an off-white foam. LCMS(M+H) + ):877.

[0322] Step 2: (8S,11S,18S)-10-[6-(3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (compound 59b) A mixture of compound 59a (245 mg, 0.224 mmol) in TFA (1 mL) and DCM (1 mL) was stirred at room temperature for 2 hours. The reaction product was then concentrated, and the residue was purified by reverse-phase flash column chromatography to obtain compound 59b (150 mg) as a white powder. LCMS(M+H + ):777.

[0323] Step 3: (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 59) To a mixture of compound 59b (30 mg, 0.39 mmol) and DIPEA (25 mg, 0.19 mmol) in dichloromethane (2 mL), cyclopropane carbonyl chloride (12 mg, 0.12 mmol) was added dropwise, and the mixture was stirred at room temperature for 1 hour. The reaction mixture was then concentrated, and the residue was purified by preparative HPLC to obtain Example 59 (18 mg) as a white powder. LCMS(M+H) + ):845. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.29-8.05 (m,1H), 7.73-7.60 (m,1H), 7.56-7.42 (m,1H), 7.21-6.98 (m,4H), 6.92-6.78 (m,1H), 6.64-6.48 (m,1H), 5.99-5.79 (m,1H), 5.39-5.32 (m,1H), 4.61- 4.33(m,8H),4.32-4.02(m,5H),4.02-3.78(m,2H),3.78-3.57(m,2H),3.39-3.30(m,2H),3. 15-2.83(m,2H),2.67-2.33(m,6H),1.79-1.63(m,1H),1.51-1.38(m,2H),1.19-1.08(m,1H).

[0324] Example 60 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0325] A mixture of compound 59b (30 mg, 0.039 mmol), 1-hydroxycyclobutanecarboxylic acid (22 mg, 0.19 mmol), DIPEA (50 mg, 0.39 mmol), and HATU (29 mg, 0.078 mmol) in DMF (2 mL) was stirred at room temperature for 1 hour. The reaction solution was then purified by preparative HPLC to obtain Example 60 (7 mg) as a white powder. LCMS(M+H + ):875. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.37-8.19 (m,1H), 7.87-7.73 (m,1H), 7.70-7.53 (m,1H), 7.37-7.04 (m,4H), 7.04-6.90 (m,1H), 6.76-6.61 (m,1H), 6.15-5.91 (m,1H), 5.57-5.30 (m,1H), 4.71-4.67 (m,1H), 4.55-4.44 (m,2 H),4.36-4.16(m,5H),4.13-3.86(m,3H),3.82-3.69(m,1H),3.52-3.40(m,2H),3.18-3.04(m,1H),3.03-3 .01(m,1H),2.79-2.41(m,8H),2.14-1.97(m,2H),1.96-1.80(m,1H),1.68-1.45(m,3H),1.35-1.15(m,2H).

[0326] Example 61 (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 61 was prepared in the same manner as in Example 59, but by using cyclopropanesulfonyl chloride instead of cyclopropanecarbonyl chloride. LCMS(M+H + ):881. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.24-8.16 (m,1H), 7.75-7.66 (m,1H), 7.55-7.46 (m,1H), 7.37-7.25 (m,1H), 7.23-7.03 (m,3H), 6.94-6.83 (m,1H), 6.69-6.59 (m,1H), 6.15-6.03 (m,1H), 5.38-5.30 (m,1H), 4.61-4.55 (m,1H), 4.48-4.36 (m,2H) ),4.27-4.18(m,3H),4.13-4.03(m,1H),4.02-3.80(m,3H),3.38-3.31(m,2H),3.07-2.95(m,2H),2.70-2.36(m,8H), 1.59-1.51(m,1H),1.50-1.35(m,1H),1.16-1.07(m,1H),0.85-0.63(m,4H),0.63-0.51(m,1H),-0.01--0.09(m,1H).

[0327] Example 62 (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] Example 62 was prepared in the same manner as in the preparation of Example 59, but by using (2,2-difluoroacetyl)2,2-difluoroacetate instead of cyclopropanecarbonyl chloride. LCMS(M+H + ):855. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.26-8.09 (m,1H), 7.74-7.61 (m,1H), 7.58-7.42 (m,1H), 7.30-7.02 (m,4H), 6.92-6.80 (m,1H), 6.66-6.54 (m,1H), 6.49-6.06 (m,1H), 6.03-5.88 (m,1H), 5.41-5.26 (m,1H), 4.63- 4.55(m,1H),4.53-4.35(m,2H),4.29-4.01(m,6H),3.95-3.85(m,1H),3.84-3.74(m,1H),3.71-3.52( m,1H),3.46-3.30(m,3H),3.07-2.98(m,1H),2.84-2.30(m,7H),1.59-1.36(m,2H),1.24-1.05(m,1H).

[0328] Examples 63 and 64 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27]Triaconta-1(27),2,4,6(30),21,23,25heptaen-12-one and (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(27),2,4,6(30),21,23,25heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0329] A mixture of intermediate C90 (83 mg, 0.21 mmol), (1-hydroxy-1H-benzotriazolato-o)tri-1-pyrrolidinyl phosphate hexafluorophosphate (138 mg, 0.27 mmol), and DIPEA (115 mg, 0.89 mmol) in N,N-dimethylformamide (2 mL) was stirred at 50°C for 3 hours. Compound 46b-1 (80 mg, 0.18 mmol) was then added, and the reaction mixture was stirred at 80°C for 2 hours. The reaction mixture was directly purified by preparative HPLC and SFC to obtain Example 63 (fast elution) and Example 64 (slow elution).

[0330] SFC conditions: Equipment: SFC 150Mgm; Column: GS Ethyl Pyridine II, inner diameter 50×20mm, 5μm; Mobile phase: A for CO2, B for ethanol (0.1%NH3H2O), gradient: B 20%; Flow rate: 80mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0331] Example 63, 14 mg, white powder. LCMS(M+H + ):805. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.33-8.10 (m,1H), 7.72-7.63 (m,1H), 7.55-7.48 (m,1H), 7.21-6.99 (m,4H), 6.91-6.76 (m,1H), 6.67-6.44 (m,1H), 6.07-5.80 (m,1H), 5.44-5.17 (m,1H) H),4.60-4.53(m,1H),4.45-4.32(m,2H),4.23-3.90(m,7H),3.80-3.71(m,2H),3.37-3 .26(m,2H),3.13-2.98(m,2H),2.79-2.41(m,8H),2.39-2.28(m,1H),1.74-1.56(m,2H).

[0332] Example 64, 11 mg, white powder. LCMS(M+H + ):805. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.29-8.15 (m,1H), 7.74-7.61 (m,1H), 7.58-7.45 (m,1H), 7.23-6.97 (m,4H), 6.96-6.78 (m,1H), 6.64-6.47 (m,1H), 6.01-5.77 (m,1H), 5.47-5.18 (m,1H), 4.59- 4.50(m,1H),4.48-4.32(m,2H),4.31-4.10(m,2H),4.09-3.87(m,5H),3.87-3.64(m,2H),3. 38-3.27(m,2H),3.17-2.99(m,2H),2.81-2.42(m,9H),2.36-2.27(m,1H),1.73-1.59(m,1H).

[0333] Cases 65 and 66 (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.12,6 .1 8,11 .1 13,18 .0 23,27 ]Triaconta-1(27),2,4,6(30),21,23,25heptaen-12-one and (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(27),2,4,6(30),21,23,25heptaen-12-one [ka] Examples 65 and 66 were prepared in the same manner as the preparations for Examples 63 and 64, but by using intermediate C91 instead of intermediate C90.

[0334] SFC conditions: Equipment: SFC 150Mgm; Column: GS Ethyl Pyridine II, inner diameter 50×20 mm, 5 μm; Mobile phase: A for CO2, B for ethanol (0.1% NH3·H2O), gradient: B 20%; Flow rate: 80 mL / min; Back pressure: 100 bar; Column temperature: 35℃.

[0335] Example 65, (rapidly eluting), 19 mg, white powder. LCMS(M+H + ):845. 1¹H NMR (400MHz, methanol-d4) δ = 8.30-8.16 (m,1H), 7.71-7.60 (m,1H), 7.57-7.49 (m,1H), 7.23-7.00 (m,4H), 6.93-6.83 (m,1H), 6.66-6.52 (m,1H), 6.01-5.89 (m,1H), 5.44-5.35 (m,1H), 4.62-4.30 (m,3 H),4.23-3.88(m,8H),3.82-3.74(m,1H),3.44-3.27(m,2H),3.09-3.05(m,1H),2.80-2.30(m,7H) ,2.13-1.89(m,1H),1.83-1.76(m,2H),1.67-1.59(m,1H),0.84-0.77(m,1H),0.06--0.25(m,4H).

[0336] Example 66, (slow elution), 16 mg, white powder. LCMS(M+H + ):845. 1 ¹H NMR (400MHz, methanol-d4) δ = 8.42-8.26 (m,1H), 7.86-7.70 (m,1H), 7.70-7.55 (m,1H), 7.38-7.08 (m,4H), 7.07-6.94 (m,1H), 6.74-6.57 (m,1H), 6.14-5.90 (m,1H), 5.59-5.34 (m,1H), 4.76-4.50 (m,3 H),4.49-4.39(m,1H),4.37-3.91(m,7H),3.91-3.80(m,1H),3.53-3.35(m,4H),3.29-3.10(m,2H) ,2.93-2.68(m,3H),2.66-2.31(m,4H),1.87-1.67(m,1H),0.93-0.54(m,1H),0.33--0.14(m,4H).

[0337] Example 67 (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.12,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0338] Step 1: Preparation of tert-butyl(1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 67b) Compound 67a (2.5 g, 11.80 mmol) was separated by SFC to obtain compound 67b-1 (1.25 g) (rapidly eluting) as a white solid and compound 67b (1.25 g) (slowly eluting) as a white solid. LCMS(M-56+H + ):157.

[0339] SFC conditions: Equipment: CASWH-Prep-SFC-H; Method Column DAICEL CHIRALPAK AD (250 mm × 30 mm, 10 μm), conditions CO2-EtOH (0.1% NH3H2O), start B40, end B40, gradient time (min) 3.9, 100% B, retention time (min) 0 flow rate (mL / min) 150.

[0340] The structure of compound 67b was confirmed by X-ray single-crystal diffraction (Figure 2).

[0341] Step 2: Preparation of benzyl(1R,5S)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 67c) To a solution of compound 67b (400 mg, 1.88 mmol) in DCM (4 mL), TFA (4.0 mL) was added at 0°C. The reaction mixture was stirred at 25°C for 1 hour and then concentrated. The residue was dissolved in THF (5 mL) and water (5 mL), and sodium carbonate (315 mg, 2.97 mmol) and N-(benzyloxycarbonyloxy)succinimide (740 mg, 2.97 mmol) were added at 0°C. The reaction mixture was stirred at 20°C for 16 hours and then diluted with water (5 mL) and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to obtain compound 67c (410 mg) as a colorless oil. LCMS(M+H + ):247.

[0342] Step 3: Preparation of benzyl(1R,5S)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate (compound 67d) To a solution of compound 67c (500.0 mg, 2.03 mmol) in DMA (8 mL), Cs2CO3 (1.32 g, 4.06 mmol) and 3-bromooxetane (1.39 g, 10.15 mmol) were added. The reaction mixture was stirred at 100°C for 12 hours. The mixture was poured into ice water and extracted with EA. The organic layer was dried and concentrated, and the residue was purified by preparative HPLC to obtain compound 67d (160.0 mg) as a colorless oil. LCMS(M+H) + ):303.

[0343] Step 4: Preparation of (1S, 5R)-3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 67e) A solution of compound 67d (160 mg, 0.53 mmol) in methanol (1 mL) was to be mixed with wet Pd / C (40 mg) under N2 at 25°C. The mixture was then heated to H 2( The mixture was stirred at 50°C for 2 hours under balloon pressure. The mixture was filtered through celite, and the filtrate was concentrated to obtain compound 67e (80 mg) as a colorless oil, which was used directly without further purification.

[0344] Step 5: (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,1 1.1 13,18 .0 23,27 Preparation of triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one (Example 67) A mixture of compound 42a-2 (40.0 mg, 0.06 mmol), compound 67f (28 mg, 0.17 mmol), CsF (42 mg, 0.28 mmol), and DIEA (0.06 mL, 0.34 mmol) in DMA (1 mL) was stirred at 120°C for 16 hours. The reaction mixture was purified by preparative HPLC to obtain Example 67 (9.0 mg) as a white solid. LCMS (M+H) + ):847. 1 H NMR (400MHz, methanol-d4)δ=8.34(s,1H),7.77(t,J=7.9Hz,1H),7.68-7.60(m,1H),7.31-7.22(m,2H),7.20-7.10(m ,2H),7.04-6.90(m,1H),6.73-6.59(m,1H),6.08-5.84(m,1H),5.53(d,J=8.5Hz,1H),5.23-5.04(m,2H),4.73(br d,J=7.6Hz,3H),4.59(s,4H),4.50-4.43(m,1H),4.25-4.09(m,4H),4.02-3.78(m,2H),3.62-3.40(m,2H),3.24-3.06 (m,2H),2.97-2.79(m,1H),2.63-2.55(m,3H),2.50-2.37(m,1H),2.04(s,1H),1.87-1.69(m,1H),1.60-1.14(m,2H).

[0345] Example 68 (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one [ka] The title compound was prepared according to the following scheme. [ka]

[0346] Step 1: Preparation of (1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-carboxylate tert-butyl (compound 68a) Compound 67b (500.0 mg, 2.36 mmol) in DCE (8 mL) solution, cyclopropylboronic acid (1 g, 11.78 mmol), sodium carbonate (499 mg, 4.71 mmol), Cu(OAc) 2( 642 mg (3.53 mmol) and 2,2'-bipyridine (552 mg, 3.53 mmol) were added at 25°C. The mixture was stirred at 80°C for 16 hours under an O2 atmosphere. The reaction mixture was then poured into water and extracted with DCM. The organic layer was dried and concentrated, and the residue was purified by silica gel column chromatography to obtain compound 68a (200.0 mg) as a colorless oil. LCMS(M-56+H + ):197.

[0347] Step 2: Preparation of (1S,5R)-3-cyclopropyl-3,6-diazabicyclo[3.1.1]heptan-2-one (compound 68b) To a solution of compound 68a (180.0 mg, 0.71 mmol) in DCM (2 mL), TFA (1.0 mL) was added at 0°C. The mixture was stirred at 25°C for 3 hours, and then concentrated to obtain compound 68b (180.0 mg) as a yellow oily substance. LCMS(M+H) + ):153.

[0348] Step 3: (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexazahexacyclo[18.6.1.1 2,6 .1 8,11 .1 13,18 .0 23,27 Preparation of Triaconta-1(26),2(30),3,5,21,23(27),24-Heptaen-12-one Example 68 was prepared in the same manner as in Example 67, but by using intermediate 68b instead of intermediate 67e. LCMS(M+H + ):831. 1H NMR (400MHz, methanol-d4)δ=8.32(s,1H),7.82-7.73(m,1H),7.68-7.59(m,1H),7.33-7.23(m,2H),7.21-7.10(m,2H),7.00- 6.94(m,1H),6.71-6.61(m,1H),6.03(dd,J=10.6,15.8Hz,1H),5.49-5.38(m,1H),4.66-4.61(m,1H),4.59(s,3H),4.53(br d,J=3.5Hz,1H),4.48-4.40(m,1H),4.32-4.24(m,1H),4.24-4.16(m,1H),4.16-4.08(m,2H),4.02(br dd,J=1.8,11.5Hz,1H),3.87(br dd,J=6.2,10.4Hz,1H),3.48-3.40(m,1H),3.30-3.23(m,1H),3.21-3.09(m,1H),2.93-2.77(m,2H),2.75-2.65(m,1H),2.62-2 .55(m,3H),2.54-2.37(m,2H),1.81-1.69(m,1H),1.57-1.47(m,1H),1.35-1.16(m,1H),0.78-0.55(m,2H),0.28-0.07(m,1H).

[0349] Example 69 Microliter plate-based TR-FRET assay for STING binders This is a competitive binding assay to test the efficacy of compounds against the C-terminal domain (CTD) and ligand-binding domain of the human interferon gene stimulator (STING). Recombinant STING (139-379, Q86WV6, http: / / www.uniprot.org / uniprot) protein with a C-terminal flag tag (expressed in 20 mM Tris, 150 mM NaCl, pH 8.0, and in *E. coli* BL21 (DE3)) was used in the assay. When the Alexa-488-labeled active site probe (see International Publication No. 2017 / 175156) binds to STING (139-379), it receives 485 nm emission from Tb-M2-Flag-STING, resulting in increased fluorescence at 520 nm. Compounds competing for the probe binding site reduce the 520 nm signal. The assay was performed using a proxy plate-384plus (Perkin-Elmer, catalog number: 60150300) containing 2.5 nM STING, 2.5 nM M2-Tb (Cisbio, 61FG2TLA, lot number: 17A), and a 250 nM Alexa488 probe. The plate was centrifuged at 1000 rpm for 1 minute, incubated at room temperature for 30 minutes, and then bifluorescence emission was measured at 520 nM / 485 nM after 320 nm laser excitation using an Envision plate reader (Perkin-Elmer). The effect of the compounds on STING binding was detected by measuring ratiometric fluorescence from time-resolved FRETs. The percentage of inhibition at each compound concentration was calculated based on their changes in TR-FRET efficiency relative to the changes in TR-FRET induced by the positive control 2'3' cGAMP (Sigma, catalog number: SML1229). [Table 3]

[0350] Example 70 THP1-Dual Lucia Reporter Gene Assay This is a cell reporter assay for evaluating the antagonistic effects of compounds on the interferon regulatory factor (IRF) pathway in THP1-Dual® cells (InvivoGen, cat.: thpd-nfis). THP1-Dual® cells were established from a human THP-1 monocyte cell line by stably incorporating the Lucia luciferase gene, a novel secreted luciferase reporter gene, under the control of the ISG54 (interferon-stimulating gene) minimal promoter and five interferon (IFN) responsive elements. As a result, THP1-Dual® cells enable the study of the IRF pathway by evaluating luciferase activity. The Lucia luciferase protein can be readily measured in the cell culture supernatant when using QUANTI-Luc® (InvivoGen, cat.: rep-qlcg-500). 2'3'cGAMP or baculovirus (double-stranded DNA virus purchased from Genescript, pCMV-Dest Vector virus generation P2 BV stock virus, Sf-900II medium containing 5% FBS, Lot C9835DK230-2 / P4DL001) was used as a stimulant to induce activation of the IRF pathway. After co-incubating THP1-Dual® cells with the compound for 20–24 hours, the antagonism and cytotoxicity of the compound against the IRF pathway were tested by measuring luminescence and OD450 using an Envision plate reader. On the day of the experiment, 25 μL of test medium (RPMI1640, 2 mM L-glutamine, 25 mM HEPES, 10% heat-inactivated fetal bovine serum) was dispensed into a white 384-well plate (Grenier, catalog number: 781098). After adding 24 μL of a stimulating agent (2'3'cGAMP with a final concentration of 20 μM, or baculovirus with a final concentration of 10 MOI), 6 μL of compound solution / well (final 1% DMSO) was transferred using Agilent Bravo. Subsequently, 30 μL of cell suspension per well (approximately 33,000 cells, 1.1 × 10⁶ cells) was added. 6Cells ( / mL) were immediately added using a Thermo Multi-Drop Combi Dispenser and incubated at 37°C, 5% CO2 for 20–24 hours. At the end of incubation, 10 μL of cell supernatant was transferred to a Proxy Plate 384-plus plate for IRF detection, and then 10 μL of QUANTI-Luc® Gold solution was added to the plate and measured immediately. To measure cell viability, 30 μL of CCK-8 working solution (Dojindo Molecular Technologies, catalog number: CK04-20) was added to the cell culture plate, incubated in an incubator for 2 hours, and then the absorbance at 450 nm was measured using Envision. [Table 4]

Claims

1. Compound of formula (I-2), 【Chemistry 1】 (In the formula, R １ H, C １－６ Alkyl or R ９ Together with it, it forms a heterogeneous ring which may be substituted, R ２ is C １－６ Alkyl or R ９ Together with, it forms a complex ring which may be substituted, M １ is a heterocyclylene which may be substituted, and further R ３ Replaced by, R ３ is 【Chemistry 2】 、 【Transformation 3】 、 【Chemistry 4】 、 【Transformation 5】 、 【Transformation 6】 、 【Transformation 7】 、 【Transformation 8】 、 【Chemistry 9】 、 【Chemistry 10】 、 【Chemistry 11】 、 【Chemistry 12】 、 【Chemistry 13】 、 【Chemistry 14】 、 【Chemistry 15】 or 【Chemistry 16】 And in the formula, R ４ H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, C １－６ Alkyl, Halo C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkylcarbonyl, C ３－７ Cycloalkylsulfonyl, Halo C １－６ Alkyl, Halo C １－６ Alkylcarbonyl, HydroxyC ３－７ 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl, R ５ is halogen, C １－６ Alkoxy, C １－６ Alkyl NH, Halo C １－６ Alkoxy, C ３－７ Cycloalkoxy and Triduterio C １－６ A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R ６ is H or C １－６ It is alkyl, A １ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ２ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ３ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ４ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ５ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ６ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ７ is N or CR ７ And in the formula, R ７ H, C １－６ Alkyl, C １－６ It is an alkoxy or halogen, A ８ is N and A ９ Is it C, or A? ８ C is A ９ Is it N, or A? ８ C is A ９ is C, Q １ CR ８ R ９ , a complex algebra that may be substituted, C ３－７ It is a cycloalkylene or oxetarnylene, in which, R ８ H, OH, C １－６ Alkoxy, halogen, CN, C １－６ Alkyl, Halo C １－６ It is alkyl, or R ９ Together with this, a substituted heteroalgebra or a substituted C ３－７ Forming a cycloalkyl ring, R ９ is H, OH, C １－６ alkoxy, halogen, CN, C １－６ alkyl, halo C １－６ alkyl, or R １ or R ２ together may form a heterocyclic ring which may be substituted, or R ８ together may form a heterocyclic ring which may be substituted or a C ３－７ cycloalkyl ring which may be substituted, Q ２ CH ２ , NH, S or O, m is 0, 1, 2, or 3. n is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

2. Compound of formula (I), 【Chemistry 17】 (In the formula, R １ is H, C １－６ alkyl, or R ９ together forms a heterocyclic ring R ２ C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ３ teeth, [Chemistry 18] And in the formula, R ４ H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, C １－６ Alkyl, Halo C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkylcarbonyl, C ３－７ Cycloalkylsulfonyl, Halo C １－６ Alkyl, Halo C １－６ Alkylcarbonyl, Hydroxy C ３－７ 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl, R ５ is halogen, C １－６ Alkoxy, Halo C １－６ Alkoxy, C ３－７ Cycloalkoxy and Triduterio C １－６ A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R ６ H is, A １ N is, A ２ is CH or N, A ３ CH is, A ４ CH is, A ５ CH is, A ６ CR ７ And in the formula, R ７ is H or halogen, A ７ CH is, A ８ is N and A ９ Is it C, or A? ８ C is A ９ is N, Q １ CR ８ R ９ , C ３－７ It is a cycloalkylene or oxetarnylene, in which, R ８ is either H or R ９ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, R ９ R １ or R ２ It forms a heterocycle together with R ８ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, Q ２ NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. or a pharmaceutically acceptable salt thereof.

3. Compound of formula (Ia), 【Chemistry 19】 (In the formula, R １ H, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ２ C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ３ teeth 【Chemistry 20】 And in the formula, R ４ H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, C １－６ Alkyl, Halo C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkylcarbonyl, C ３－７ Cycloalkylsulfonyl, Halo C １－６ Alkyl, Halo C １－６ Alkylcarbonyl, Hydroxy C ３－７ 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl, R ５ is halogen, C １－６ Alkoxy, Halo C １－６ Alkoxy, C ３－７ Cycloalkoxy and Triduterio C １－６ A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R ６ H is, A １ N is, A ２ is CH or N, A ３ CH is, A ４ CH is, A ５ CH is, A ６ CR ７ And in the formula, R ７ is H or halogen, A ７ CH is, A ８ is N and A ９ Is it C, or A? ８ C is A ９ is N, Q １ CR ８ R ９ , C ３－７ It is a cycloalkylene or oxetarnylene, in which, R ８ is either H or R ９ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, R ９ R １ or R ２ It forms a heterocycle together with R ８ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, Q ２ NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. a compound according to claim 1 or 2, or a pharmaceutically acceptable salt thereof.

4. Compound of formula (I-1), 【Chemistry 21】 (In the formula, R １ H, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ２ C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ３ teeth, 【Chemistry 22】 And in the formula, R ４ H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, C １－６ Alkyl, Halo C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkylcarbonyl, C ３－７ Cycloalkylsulfonyl, Halo C １－６ Alkyl, Halo C １－６ Alkylcarbonyl, Hydroxy C ３－７ 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl, R ５ is halogen, C １－６ Alkoxy, Halo C １－６ Alkoxy, C ３－７ Cycloalkoxy and Triduterio C １－６ A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R ６ H is, A １ N is, A ２ is CH or N, A ３ CH is, A ４ CH is, A ５ CH is, A ６ CR ７ And in the formula, R ７ is H or halogen, A ７ CH is, Q １ CR ８ R ９ , C ３－７ It is a cycloalkylene or oxetarnylene, in which, R ８ is either H or R ９ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, R ９ R １ or R ２ It forms a heterocycle together with R ８ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, Q ２ NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. a compound according to any one of claims 1 to 3, or a pharmaceutically acceptable salt thereof.

5. Compound of formula (I-1a), 【Chemistry 23】 (In the formula, R １ H, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ２ C １－６ Alkyl or R ９ Together with it, it forms a complex ring, R ３ teeth, 【Chemistry 24】 And in the formula, R ４ H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, C １－６ Alkyl, Halo C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkylcarbonyl, C ３－７ Cycloalkylsulfonyl, Halo C １－６ Alkyl, Halo C １－６ Alkylcarbonyl, Hydroxy C ３－７ 3,6-diazabicyclo[3.1.1]heptanyl substituted with cycloalkylcarbonyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl, R ５ is halogen, C １－６ Alkoxy, Halo C １－６ Alkoxy, C ３－７ Cycloalkoxy and Triduterio C １－６ A phenyl compound that is substituted once, twice, or three times with a substituent independently selected from the alkoxy, R ６ H is, A １ N is, A ２ is CH or N, A ３ CH is, A ４ CH is, A ５ CH is, A ６ CR ７ And in the formula, R ７ is H or halogen, A ７ CH is, Q １ CR ８ R ９ , C ３－７ It is a cycloalkylene or oxetarnylene, in which, R ８ is either H or R ９ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, R ９ R １ or R ２ It forms a heterocycle together with R ８ Together with it, it forms a complex algebra or C ３－７ Forming a cycloalkyl ring, Q ２ NH is, m is 0, 1, 2, or 3. n is 0, 1, or 2. a compound according to any one of claims 1 to 4, or a pharmaceutically acceptable salt thereof.

6. R １ However, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, in the formula R １ C １－６ It is alkylene, R ９ is, -C １－６ The compound according to any one of claims 1 to 5, wherein it is alkylene-O-.

7. R １ However, is it methyl, or R ９ Together with it, it forms a complex ring, in the formula R １ is methylene, and R ９ The compound according to any one of claims 1 to 6, wherein is -methylene-O-.

8. R ２ However, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, in the formula R ２ C １－６ It is alkylene, R ９ is a bond, O or -C １－６ The compound according to any one of claims 1 to 7, wherein it is alkylene-O-.

9. R ２ However, is it methyl, or R ９ Together with it, it forms a complex ring, in the formula R ２ is ethylene or propylene, and R ９ The compound according to any one of claims 1 to 8, wherein is a bond, O, or -methylene-O-.

10. R ４ However, H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, Hello C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, Hello C １－６ 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl. The compound according to any one of claims 1 to 9.

11. R ４ However, H, [1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(oxetane-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptane-6-yl, 3-(oxetane-3-yl)-3,6-diazabicyclo[3.1.1]heptane The compound according to any one of claims 1 to 10, wherein the compound is -6-yl, 3-cyanoazetidine-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl, or methyl.

12. R ５ However, halogen, C １－６ Alkoxy and triduterio C １－６ The compound according to any one of claims 1 to 11, wherein the compound is a phenyl compound that is twice substituted with a substituent independently selected from the alkoxy.

13. R ５ The compound according to any one of claims 1 to 12, wherein the compound is a phenyl compound that is twice substituted with a substituent independently selected from fluoro, methoxy, and triduteriomethoxy.

14. R ５ The compound according to any one of claims 1 to 13, wherein the compound is 2,4-difluorophenyl, 4-fluoro-2-methoxyphenyl, or 4-fluoro-2-(triduteriomethoxy)phenyl.

15. R ７ The compound according to any one of claims 1 to 14, wherein the compound is H or fluoro.

16. Q １ However, CR ８ R ９ The compound according to any one of claims 1 to 15.

17. R ８ The compound according to any one of claims 1 to 16, wherein H is present.

18. The compound according to any one of claims 1 to 17, wherein m is 0, 1, or 2.

19. R １ However, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, in the formula R １ C １－６ It is alkylene, R ９ is, -C １－６ It is alkylene-O-, R ２ However, C １－６ Alkyl or R ９ Together with it, it forms a complex ring, in the formula R ２ C １－６ It is alkylene, R ９ is a bond, O or -C １－６ It is alkylene-O-, R ３ but, 【Chemistry 25】 And in the formula, R ４ H, ((Hello C １－６ Alkyl) Azetidinyl) C １－６ Alkyl, Hello C １－６ 2,5-diazabicyclo[2.2.1]heptanyl substituted with alkyl or oxetanyl, C １－６ Alkyl, C ３－７ Cycloalkyl, C ３－７ Cycloalkyl C １－６ 2-oxo-3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, Hello C １－６ 3,6-diazabicyclo[3.1.1]heptanyl substituted with alkyl or oxetanyl, 3-Oxa-6-azabicyclo[3.1.1]heptanyl, C １－６ Alkoxy C １－６ Alkyl, C １－６ alkyl, or It is cyanoazetidinyl, R ５ is halogen, C １－６ Alkoxy and triduterio C １－６ A phenyl compound that is twice substituted with substituents independently selected from the alkoxy, R ６ H is, A １ N is, A ２ is CH or N, A ３ CH is, A ４ CH is, A ５ CH is, A ６ CR ７ And in the formula, R ７ is H or halogen, A ７ CH is, Q １ CR ８ R ９ And in the formula, R ８ H is R ９ R １ or R ２ Together with it, it forms a complex ring, Q ２ NH is, m is 0, 1, or 2. n is 0, 1, or 2, where m and n are not both 0 at the same time. A compound according to any one of claims 1 to 5, or a pharmaceutically acceptable salt thereof.

20. R １ However, is it methyl, or R ９ Together with it, it forms a complex ring, in the formula R １ is methylene, and R ９ It is -methylene-O-, R ２ However, is it methyl, or R ９ Together with it, it forms a complex ring, in the formula R ２ is ethylene or propylene, and R ９ It is a bond, O or -methylene-O-, R ３ but, 【Chemistry 26】 And in the formula, R ４ H is [1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl, 3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-(oxetan-3-yl)-3,6-diazabicyclo [3.1.1]heptan-6-yl, 3-cyanoazetidine-1-yl, 3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl, 3-oxa-6-azabicyclo[3.1.1]heptan-6-yl, 5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, 5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl, methoxymethyl or methyl, R ５ These are 2,4-difluorophenyl, 4-fluoro-2-methoxyphenyl, or 4-fluoro-2-(triduteriomethoxy)phenyl, R ６ H is, A １ N is, A ２ is CH or N, A ３ CH is, A ４ CH is, A ５ CH is, A ６ CR ７ And in the formula, R ７ is H or fluoro, A ７ CH is, Q １ CR ８ R ９ And in the formula, R ８ H is R ９ R １ or R ２ Together with it, it forms a complex ring, Q ２ NH is, m is 0, 1, or 2. n is 0, 1, or 2, where m and n are not both 0 at the same time. The compound according to claim 19, or a pharmaceutically acceptable salt thereof.

21. (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1 ２，６ 1. ８，１１ 1. １３，１７ . 0 ２２，２６ ]nonacosa-1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-20-methyl-16-oxa-7,10,13,19,21,29-hexaazahexacyclo[[17.6.1.1 ２，６ 1. ８，１１ 1. １３，１７ . 0 ２２，２６ ]nonacosa-1(26),2,4,6(29),20,22,24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,17S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-7,10,13,20,22,29-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ . 0 １３，１７ . 0 ２３，２７ ] nonacosa-1(26),2(29),3,5,21,23(27),24-heptaen-12-on; (8S,11S,17R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-7,10,13,20,22,29-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ . 0 １３，１７ . 0 ２３，２７ ] nonacosa-1(26),2(29),3,5,21,23(27),24-heptaen-12-on; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexaazahexacyclo[19.6.1.1 ２，６ 1. ８，１１ . 0 １３，１８ . 0 ２４，２８ ] Triaconta-1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-26-fluoro-22-methyl-16-oxa-7,10,13,21,23,30-hexaazahexacyclo[19.6.1.1 ２，６ 1. ８，１１ . 0 １３，１８ . 0 ２４，２８ ] Triaconta-1(27),2(30),3,5,22,24(28),25-heptaen-12-one; (8S,11S,16R)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,18,20,28-hexaazahexacyclo[16.6.1.1 ２，６ 1. ８，１１ 1. １３，１６ . 0 ２１，２５ Octacosa-1(24),2(28),3,5,19,21(25),22-heptaen-12-one; (2R,5R,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1 ２，５ 1. ８，１１ 1. １３，１７ . 0 ２２，２５ Octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one; (2S,5S,8S,11S)-9-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-6-methyl-1,6,9,12,23,26-hexaazahexacyclo[16.6.1.1 ２，５ 1. ８，１１ 1. １３，１７ . 0 ２２，２５ Octacosa-13,15,17(26),18,20,22(25),23-heptaen-7-one; (8S,11S)-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-13,18-dimethyl-spiro[7,10,13,17,19,26-hexaazopentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,3'-oxetane]-12-one; (8S,11S,18S)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-[2-(difluoromethoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18R)-10-[1-[2-(cyclopropoxy)-4-fluorophenyl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2-ethoxy-4-fluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)-6-methyl-pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-(4-fluoro-2-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(methoxymethyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-5,7,10,13,20,22,30-heptazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-16-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１７ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluoro-6-methoxyphenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18R)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-methyl-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-methyl-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; ((8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-22-fluoro-13,18-dimethyl-spiro[7,10,13,17,19,26-hexazapentacyclo[15.6.1.1 ２，６ 1. ８，１１ . 0 ２０，２４ ]Hexacosa-1(23),2(26),3,5,18,20(24),21-heptaene-15,1'-cyclopropane]-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-(3-oxa-6-azabicyclo[3.1.1]heptan-6-yl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (13R,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ . 0 ８，１３ ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaene-17-on; (13S,18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-11-oxa-8,16,19,22,27,29-hexaazahexacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ . 0 ８，１３ ]nonacosa-1(26),2(7),3,5,9(29),23(27),24-heptaene-17-on; (18S,21S)-19-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-16-methyl-9,12,16,19,22,27,29-heptazahexacyclo[21.3.1.1 ６，９ 1. １８，２１ . 0 ２，７ . 0 ８，１３ ] Nonacosa-1(26),2,4,6(29),7,23(27),24-heptaene-11,17-zion; (8S,11S)-10-[1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-7,10,13,16,22,24,31-heptazahexacyclo[20.6.1.1 ２，６ 1. ８，１１ . 0 １３，１８ . 0 ２５，２９ ] Hentriakonta-1(29),2,4,6(31),23,25,27-heptaen-12-one; (8S,11S,18S)-25-fluoro-10-[1-[4-fluoro-2-(triduteriomethoxy)phenyl]-6-[[1-(2,2,2-trifluoroethyl)azetidine-3-yl]methyl]pyrazolo[3,4-d]pyrimidine-4-yl]-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(2-fluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(2-fluoroethyl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(oxetan-3-yl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroethyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,4R)-5-(oxetan-3-yl)-2,5-diazabicyclo[2.2.1]heptan-2-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; 1-[1-(2,4-difluorophenyl)-4-[(8S,11S,18S)-25-fluoro-21-methyl-12-oxo-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-10-yl]pyrazolo[3,4-d]pyrimidine-6-yl]azetidine-3-carbonitriel; (8S,11S,18S)-10-[6-[3-(cyclopropanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[3-(1-hydroxycyclobutanecarbonyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-(3-cyclopropylsulfonyl-3,6-diazabicyclo[3.1.1]heptan-6-yl)-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[6-[3-(2,2-difluoroacetyl)-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1R,5S)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-methyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1R,5S)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[6-[(1S,5R)-3-(cyclopropylmethyl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ] Triaconta-1(27),2,4,6(30),21,23,25-heptaen-12-one; (8S,11S,18S)-10-[1-(2,4-difluorophenyl)-6-[(1S,5R)-3-(oxetan-3-yl)-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one; and (8S,11S,18S)-10-[6-[(1S,5R)-3-cyclopropyl-2-oxo-3,6-diazabicyclo[3.1.1]heptan-6-yl]-1-(2,4-difluorophenyl)pyrazolo[3,4-d]pyrimidine-4-yl]-25-fluoro-21-methyl-17-oxa-7,10,13,20,22,30-hexaazahexacyclo[18.6.1.1 ２，６ 1. ８，１１ 1. １３，１８ . 0 ２３，２７ ]Triaconta-1(26),2(30),3,5,21,23(27),24-heptaen-12-one A compound selected from, or a pharmaceutically acceptable salt thereof.

22. A method for preparing a compound according to any one of claims 1 to 21, comprising the following steps: a) Compound of formula (VI) in the presence of a base 【Chemistry 27】 and R ３ The compound of formula (VI) and R via nucleophilic substitution with X, or in the presence of a coupling reagent. ３ Formation of the compound of formula (I) via a condensation reaction with OH, b) R ４ Compounds of (Ic) when containing a reactive primary or secondary amino group 【Chemistry 28】 and R ４ A compound of formula (Ic) and a halide R via nucleophilic substitution with H, or in the presence of a catalyst. ４ X or XR ｃ Compound of formula (IX) via photoredox coupling with BoC 【Chemistry 29】 Formation, c) Compound of formula (VIII) 【Transformation 30】 The process includes the formation of a compound of formula (IX) via a reaction between a halide, an acid anhydride, or acid, In the formula, X is a halogen, and R ｅ is a divalent substituent having a reactive primary or secondary amino group, The base in step a) is DIEA, The coupling reagent in step a) is PyBOP. The catalyst in step b) is Ir[dF(CF ３ )ppy] ２ (dtbbpy)PF ６ And, R １ ~R ５ Q １ Q ２ A １ ~A ７ A method as defined in any one of claims 1 to 20.

23. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for use as a therapeutically active substance.

24. A pharmaceutical composition comprising a compound according to any one of claims 1 to 21 and a pharmaceutically acceptable excipient.

25. Use of the compound according to any one of claims 1 to 21 for treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer involving overexpression or activation of STING.

26. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21 for preparing a pharmaceutical product for treating or preventing autoimmune diseases, inflammatory diseases, neurological disorders, metabolic diseases, cardiovascular diseases, ocular diseases, or selective types of cancer involving the overexpression or activation of STING.

27. Use of the compound according to any one of claims 1 to 21 for the treatment of subjects suffering from interferon disorders or autoinflammatory diseases in which STING activation is the underlying cause of the disease pathology.

28. Use of any one of the compounds according to claims 1 to 21 for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial chilblain-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Gutierrez syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

29. Use of the compound according to any one of claims 1 to 21 for preparing a pharmaceutical product for the treatment or prevention of systemic lupus erythematosus (SLE), dermatomyositis, diabetic nephropathy (DKD), diabetic retinopathy (DR), age-related macular degeneration (AMD), antineutrophil cytoplasmic autoantibody (ANCA) vasculitis, infant-onset STING-associated vascular disease (SAVI), familial chilblain-like lupus (FCL), Niemann-Pick disease type C (NPC), Aicardi-Gutierrez syndrome (AGS), COPA syndrome, or Wiscott-Aldrich syndrome.

30. Use of a compound according to any one of claims 1 to 21 for inhibiting STING.

31. Use of a compound according to any one of claims 1 to 21 for preparing a pharmaceutical product for inhibiting STING.

32. A compound or pharmaceutically acceptable salt according to any one of claims 1 to 21, when produced according to the process described in claim 22.

33. A method for treating or preventing an autoimmune disease, comprising administering a therapeutically effective amount of the compound described in any one of claims 1 to 21.

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